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Cited by 158Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

Open access
Wang, Shuang, Friedman, Scott L.·2023·Science Translational Medicine
DOI 10.1126/scitranslmed.adi0759PMC PMC10671253
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Abstract

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses a global health threat because of its potential to progress to advanced fibrosis, leading to cirrhosis and liver cancer. Recent advances in single-cell methodologies, refined disease models, and genetic and epigenetic insights have provided a nuanced understanding of MASH fibrogenesis, with substantial cellular heterogeneity in MASH livers providing potentially targetable cell-cell interactions and behavior. Unlike fibrogenesis, mechanisms underlying fibrosis regression in MASH are still inadequately understood, although antifibrotic targets have been recently identified. A refined antifibrotic treatment framework could lead to noninvasive assessment and targeted therapies that preserve hepatocellular function and restore the liver’s architectural integrity.

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Crossref · 10.1126/scitranslmed.adi0759

Cites

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Claims the paper makes

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  • Findingown data

    Our single-nuclear RNA-seq in murine MASH models and MASH patients showed enrichment of myofibroblast pathways regulating ECM production and cell migration, including MMPs, TIMPs, and LOXLs.

    “We recently used single nuclear RNA-seq in murine MASH models and patients with MASH to demonstrate enrichment of pathways in myofibroblasts that regulate extracellular matrix production and cell migration, including matrix metalloproteinase (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and lysyl oxidases (LOXLs) (47-49), similar to earlier studies of mouse fibrosis and human cirrhosis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] Wang Z-Y, Keogh A, Waldt A, Cuttat R, Neri M, Zhu S, Schuierer S, Ruchti A, Crochemore C, Knehr J, Bastien J, Ksiazek I, Sánchez-Taltavull D, Ge H, Wu J, Roma G, Helliwell SB, Stroka D, Nigsch F, Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci Rep-Uk 11, 19396 (2021). PMC8481490 34588551 source

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    • cites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source

      Not checked in the free run.

    • cites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

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  • Findingown data

    Informatic subsetting of purified HSCs from the foz/foz mouse model revealed three activated clusters and one inactivated cluster with different transcript abundances of Acta2, Col1a1, and Timp1.

    “Further informatic subsetting of purified HSCs in the foz/foz mouse model revealed 3 distinct activated cell clusters and 1 inactivated cell cluster, expressing different abundances of classical myofibroblast markers such as alpha smooth muscle actin (Acta2), collagen type 1 alpha 1 (Col1a1), and tissue inhibitors of metalloproteinase 1 (Timp1) at the transcript level.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Progressive liver injury changes the amount and composition of extracellular matrix, with fibrillar collagen types I and III first accumulating in the subendothelial space and later forming collagen bands.

    “Progressive injury leads to changes in the quality and quantity of ECM with accumulation of fibrillar collagen (primarily types I and III) initially within the subendothelial space, which coalesce over years to form fibrils that generate bands of collagen.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    ECM accumulation increases liver stiffness at both macroscopic and microscopic scales.

    “Specifically, accumulation of ECM increases the stiffness of the liver both macro- and microscopically.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    Once fibrosis distorts liver architecture and disrupts blood flow and oxygenation, functional and regenerative capacity is impaired enough to be detected by INR, albumin, and platelet count.

    “Once fibrosis begins to distort the liver’s architecture, disrupting blood flow and oxygenation of the tissue, the functional and regenerative capacity of liver is impaired to an extent detectable by routine tests including INR, albumin, and platelet count, among others.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 120
  • Classified as probably not a substantial claim. 44

  • May combine two claims.

    Findingcitation

    Our single-nucleus RNA-seq profiling of FAT-MASH macrophages showed no enrichment of ECM-related pathways, only induction of MMP2, MMP12, and MMP14 and decreased COL18A1.

    “Our profiling of FAT-MASH macrophages using single nucleus RNA-seq showed no enrichment of ECM-related pathways, only induction of a few select matrix metalloproteinases (MMP2, matrix metalloproteinase 12 (MMP12), matrix metalloproteinase 14 (MMP14)) and decreased collagen type 18 alpha 1 (COL18A1) (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The amount of fibrosis is the strongest predictor of death in MASH patients and is therefore the main target of drug development.

    “Among these features, the extent of fibrosis is the strongest predictor of patient mortality, and is therefore the focus of drug development efforts (13-16).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, Hultcrantz R, Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61, 1547– 1554 (2015). 25125077 source

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    • cites [14] Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, Kechagias S, Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. Journal of Hepatology 67, 1265– 1273 (2017). 28803953 source

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    • cites [15] Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F, Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 149, 389– 397.e310 (2015). 25935633 PMC4516664 source

      Not checked in the free run.

    • cites [16] Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW-S, Kechagias S, Hultcrantz R, Loomba R, Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65, 1557– 1565 (2017). 28130788 PMC5397356 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No drugs are approved for MASH, making it a major unmet medical need.

    “Despite the scale and urgency of the disease, there are currently no approved drugs for MASH, making it a major unmet need (3, 12).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source

      Not checked in the free run.

    • cites [12] Rowe IA, Wong VW, Loomba R, Treatment Candidacy for Pharmacologic Therapies for NASH. Clin Gastroenterol Hepatol 20, 1209– 1217 (2022). 33711479 PMC8908435 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased stiffness of the pericellular environment activates hepatic stellate cells and raises their fibrogenic activity.

    “Microscopically, the enhanced stiffness of the pericellular milieu affects all cells, most notably by activating hepatic stellate cells (HSCs) to increase their fibrogenic activity (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, Mick R, Janmey PA, Furth EE, Wells RG, Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293, G1147– 1154 (2007). 17932231 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MASH is a severe form of MASLD associated with inflammation and fibrosis and can progress to advanced fibrosis, cirrhosis, and liver cancer.

    “metabolic dysfunction-associated steatohepatitis (MASH or previously non-alcoholic steatohepatitis/NASH), which is associated with inflammation and fibrosis (1-4).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Hossain P, Kawar B, El Nahas M, Obesity and Diabetes in the Developing World — A Growing Challenge. New England Journal of Medicine 356, 213– 215 (2007). 17229948 source

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    • cites [2] Diehl AM, Day C, Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. New England Journal of Medicine 377, 2063– 2072 (2017). 29166236 source

      Not checked in the free run.

    • cites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source

      Not checked in the free run.

    • cites [4] Loomba R, Friedman SL, Shulman GI, Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537– 2564 (2021). 33989548 PMC12168897 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    ECM can form a physical barrier to trans-sinusoidal transport and disrupt the function of sinusoidal endothelial cells.

    “ECM may also generate a physical barrier to trans-sinusoidal transport (‘capillarization’) and concurrently disrupt the function of other resident liver cells besides hepatocytes, in particular sinusoidal endothelial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Progressive functional changes likely occur throughout MASH progression, but current diagnostic tests are not sensitive enough to detect them until marked architectural disruption is present.

    “There likely are progressive functional changes throughout the course of MASH progression, but current diagnostic tests are not sufficiently sensitive to detect them until they are accompanied by marked architectural disruption.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Current diagnostic tests lack the sensitivity to detect progressive functional changes in MASH before marked architectural disruption occurs.

  • May combine two claims.

    Premisecitation

    Changes in the matrisome affect all ECM molecule families and alter the biochemical and mechanical properties of the liver.

    “Progressive changes in the composition of the matrisome affect all families of ECM molecules (17, 18), leading to altered biochemical and mechanical features of the liver.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Dolin CE, Arteel GE, The Matrisome, Inflammation, and Liver Disease. Semin Liver Dis 40, 180– 188 (2020). 31910448 PMC7195244 source

      Not checked in the free run.

    • cites [18] Massey VL, Dolin CE, Poole LG, Hudson SV, Siow DL, Brock GN, Merchant ML, Wilkey DW, Arteel GE, The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice. Hepatology 65, 969– 982 (2017). 28035785 PMC5319876 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In non-cirrhotic stages, soluble signals from the changing ECM or fibrogenic cells can impair regeneration, disturb immune homeostasis, and alter clearance of systemic and hepatic metabolites.

    “In non-cirrhotic stages, soluble signals from the changing ECM composition or fibrogenic cells can impede regeneration, disrupt immune homeostasis, and alter the clearance of systemic and hepatic metabolites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Myofibroblasts are the main fibrogenic cells in fibrotic liver and are derived from resident mesenchymal pericytes, or HSCs.

    “Similar to other tissues, myofibroblasts are the main fibrogenic cells in fibrotic liver. In liver they are derived from resident mesenchymal pericytes, or HSCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hepatic progenitor cells are typically present in ductular reactions and can be a source of TGFβ and PDGF, which are potent activating stimuli.

    “Hepatic progenitor cells are typically present within ductular reactions and represent a potential source of transforming growth factor beta (TGFβ and platelet-derived growth factor (PDGF), potent activating stimuli (34-36).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Ramm GA, Nair VG, Bridle KR, Shepherd RW, Crawford DHG, Contribution of Hepatic Parenchymal and Nonparenchymal Cells to Hepatic Fibrogenesis in Biliary Atresia. The American Journal of Pathology 153, 527– 535 (1998). 9708812 PMC1852970 source

      Not checked in the free run.

    • cites [35] Grappone C, Pinzani M, Parola M, Pellegrini G, Caligiuri A, DeFranco R, Marra F, Herbst H, Alpini G, Milani S, Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. Journal of Hepatology 31, 100– 109 (1999). 10424289 source

      Not checked in the free run.

    • cites [36] Malizia G, Brunt EM, Peters MG, Rizzo A, Broekelmann TJ, McDonald JA, Growth factor and procollagen type I gene expression in human liver disease. Gastroenterology 108, 145– 156 (1995). 7806036 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Only drugs that target upstream hepatic lipid accumulation pathways, and not downstream mediators of cell injury or death, have shown signs of clinical efficacy.

    “Thus far only drugs targeting upstream hepatic lipid accumulation pathways but none of the downstream mediators of cell injury and cell death show signs of efficacy in the clinic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Ductular reaction is frequent in MASH and strongly correlates with fibrosis severity in patients, for reasons that remain unclear.

    “Ductular reaction in MASH is frequent and strongly correlates with fibrosis severity in patients for unclear reasons (32, 33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander–Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, Clouston AD, Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction. Gastroenterology 133, 80– 90 (2007). 17631134 source

      Not checked in the free run.

    • cites [33] Zhao L, Westerhoff M, Pai RK, Choi W-T, Gao Z-H, Hart J, Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis. Modern Pathology 31, 150– 159 (2018). 28862262 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sustained myofibroblast activation in chronic liver disease drives fibrosis, especially in MASH, where myofibroblasts are detectable by desmin and αSMA immunofluorescence and by single-cell RNA-seq gene expression.

    “These functions normally contribute to tissue repair under homeostatic conditions, but sustained activation in chronic liver diseases drives fibrosis, especially in MASH (41) where they are detectable by expression of desmin and alpha smooth muscle actin (αSMA) using immunofluorescence, and by conservation of gene expression based on single-cell RNA-seq (42-46).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [41] Schuster R, Younesi F, Ezzo M, Hinz B, The Role of Myofibroblasts in Physiological and Pathological Tissue Repair. Cold Spring Harbor Perspectives in Biology, (2022). PMC9808581 36123034 source

      Not checked in the free run.

    • cites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 source

      Not checked in the free run.

    • cites [43] Ganguly S, Muench GA, Shang L, Rosenthal SB, Rahman G, Wang R, Wang Y, Kwon HC, Diomino AM, Kisseleva T, Soorosh P, Hosseini M, Knight R, Schnabl B, Brenner DA, Dhar D, Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet. Cellular and Molecular Gastroenterology and Hepatology 12, 891– 920 (2021). 34062281 PMC8342972 source

      Not checked in the free run.

    • cites [44] Marcher A-B, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K, Transcriptional regulation of Hepatic Stellate Cell activation in NASH. Sci Rep-Uk 9, 2324 (2019). PMC6382845 30787418 source

      Not checked in the free run.

    • cites [45] Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S, Fiel MI, Goossens N, Chou H-I, Hoshida Y, Friedman SL, A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of Hepatology 69, 385– 395 (2018). 29572095 PMC6054570 source

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  • May combine two claims.

    Premisecitation

    Other myofibroblast sources include vascular smooth muscle cells, mesothelial cells, and portal fibroblasts; portal myofibroblasts marked by THY1 may play an outsized role in biliary fibrosis because of their portal location.

    “Other sources of myofibroblasts include vascular smooth muscle cells, mesothelial cells, and portal fibroblasts, out of which portal myofibroblasts marked by thymocyte differentiation antigen 1 (THY1) may play an outsized role in biliary fibrosis due to their physical localization in the portal region (53, 55-57) (58).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [53] Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere J-P, Schwabe RF, Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature communications 4, 2823 (2013). PMC4059406 24264436 source

      Not checked in the free run.

    • cites [55] Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF, Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073– 1083 e1022 (2012). 22750464 PMC3848328 source

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    • cites [56] Yang W, He H, Wang T, Su N, Zhang F, Jiang K, Zhu J, Zhang C, Niu K, Wang L, Yuan X, Liu N, Li L, Wei W, Hu J, Single-Cell Transcriptomic Analysis Reveals a Hepatic Stellate Cell–Activation Roadmap and Myofibroblast Origin During Liver Fibrosis in Mice. Hepatology 74, 2774– 2790 (2021). 34089528 PMC8597108 source

      Not checked in the free run.

    • cites [57] Lei L, Bruneau A, El Mourabit H, Guegan J, Folseraas T, Lemoinne S, Karlsen TH, Hoareau B, Morichon R, Gonzalez-Sanchez E, Goumard C, Ratziu V, Charbord P, Gautheron J, Tacke F, Jaffredo T, Cadoret A, Housset C, Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis. Hepatology 76, 1360– 1375 (2022). 35278227 source

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    • cites [58] Katsumata LW, Miyajima A, Itoh T, Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury. Hepatol Commun 1, 198– 214 (2017). 29404454 PMC5721447 source

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  • May combine two claims.

    Premisecitation

    Most myofibroblasts in chemically injured mouse models come from HSCs, and depleting them reduces liver fibrosis.

    “The majority of myofibroblasts in chemically-injured mouse models also derive from HSCs, and their depletion reduces liver fibrosis (52-54).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [52] Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF, Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice. Gastroenterology 143, 1073– 1083.e1022 (2012). 22750464 PMC3848328 source

      Not checked in the free run.

    • cites [53] Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere J-P, Schwabe RF, Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature communications 4, 2823 (2013). PMC4059406 24264436 source

      Not checked in the free run.

    • cites [54] Puche JE, Lee YA, Jiao J, Aloman C, Fiel MI, Muñoz U, Kraus T, Lee T, Yee HF Jr, Friedman SL, A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice. Hepatology 57, 339– 350 (2013). 22961591 PMC3522764 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NK cytotoxicity may be enhanced by mucosal invariant T cells.

    “NK cytotoxicity may be enhanced by mucosal invariant T (MAIT) cells (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Jiang X, Peng Y, Liu L, Wang Y, Li M, Li W, Huang F, Zheng C, Xu F, Hu Q, Wei W, Dong S, Zhao Q, MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver international: official journal of the International Association for the Study of the Liver 42, 2743– 2758 (2022). 36181707 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In damaged and inflammatory liver, quiescent HSCs activate into proliferative, contractile, ECM-remodeling myofibroblasts that also secrete cytokines and chemokines.

    “In the presence of signals from the damaged and inflammatory liver, quiescent HSCs “activate” into proliferative, contractile, ECM-remodeling myofibroblasts that also harbor inflammatory features through the secretion of cytokines and chemokines (96) (97, 98).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [96] Tsuchida T, Friedman SL, Mechanisms of hepatic stellate cell activation. Nature Reviews Gastroenterology & Hepatology 14, 397– 411 (2017). 28487545 source

      Not checked in the free run.

    • cites [97] Filliol A, Saito Y, Nair A, Dapito DH, Yu LX, Ravichandra A, Bhattacharjee S, Affo S, Fujiwara N, Su H, Sun Q, Savage TM, Wilson-Kanamori JR, Caviglia JM, Chin L, Chen D, Wang X, Caruso S, Kang JK, Amin AD, Wallace S, Dobie R, Yin D, Rodriguez-Fiallos OM, Yin C, Mehal A, Izar B, Friedman RA, Wells RG, Pajvani UB, Hoshida Y, Remotti HE, Arpaia N, Zucman-Rossi J, Karin M, Henderson NC, Tabas I, Schwabe RF, Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356– 365 (2022). 36198802 PMC9949942 source

      Not checked in the free run.

    • cites [98] Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M, Chin L, Filliol A, Wen W, Song X, Decker A, Worley J, Caviglia JM, Yu L, Yin D, Saito Y, Savage T, Wells RG, Mack M, Zender L, Arpaia N, Remotti HE, Rabadan R, Sims P, Leblond AL, Weber A, Riener MO, Stockwell BR, Gaublomme J, Llovet JM, Kalluri R, Michalopoulos GK, Seki E, Sia D, Chen X, Califano A, Schwabe RF, Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 866– 882 e811 (2021). 33930309 PMC8241235 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In fatty liver, lipid-associated macrophages have a unique ability to metabolize lipids, but their contribution to fibrosis is unknown.

    “In fatty liver, a novel subset of lipid-associated macrophages (LAMs) display a unique ability to metabolize lipids, but their contribution to fibrosis is unknown (70, 76).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Remmerie A, Martens L, Thoné T, Castoldi A, Seurinck R, Pavie B, Roels J, Vanneste B, De Prijck S, Vanhockerhout M, Binte Abdul Latib M, Devisscher L, Hoorens A, Bonnardel J, Vandamme N, Kremer A, Borghgraef P, Van Vlierberghe H, Lippens S, Pearce E, Saeys Y, Scott CL, Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver. Immunity 53, 641– 657.e614 (2020). 32888418 PMC7501731 source

      Not checked in the free run.

    • cites [76] Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I, Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 178, 686– 698.e614 (2019). 31257031 PMC7068689 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Quiescent HSCs are pericyte-like cells that wrap around vasculature, support homeostatic hepatocyte turnover via growth factors such as HGF, and store vitamin A.

    “HSCs normally exist as quiescent pericyte-like cells that wrap around the vasculature, promote homeostatic hepatocyte turnover through the secretion of growth factors such as hepatocyte growth factor (HGF), and serve as a major storage site for vitamin A.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Macrophages, including Kupffer cells and recruited monocyte-derived cells, secrete cytokines that activate HSCs into myofibroblasts, with TGFβ being the most potent.

    “Macrophages, both the liver resident Kupffer cells and bone marrow monocyte-derived cells recruited in response to injury, secrete cytokines that activate HSCs into myofibroblasts, the most potent of which being TGFβ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HSC-NK crosstalk is bidirectional; activated HSCs can disrupt liver cancer dormancy by secreting CXCL12, which induces NK quiescence and reduces cancer cell killing.

    “The HSC-NK cell crosstalk is bidirectional, as activated HSCs can also disrupt cancer dormancy in liver through their secretion of C-X-C motif chemokine 12 (CXCL12) to induce NK cell quiescence that reduces cancer cell killing (94).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Correia AL, Guimaraes JC, Auf der Maur P, De Silva D, Trefny MP, Okamoto R, Bruno S, Schmidt A, Mertz K, Volkmann K, Terracciano L, Zippelius A, Vetter M, Kurzeder C, Weber WP, Bentires-Alj M, Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature 594, 566– 571 (2021). 34079127 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Monocyte-derived macrophages replace Kupffer cells that normally clear iron, causing iron overload, oxidative stress, and activation of HSCs into myofibroblasts.

    “Second, monocyte-derived macrophages replace liver resident Kupffer cells that normally clear iron, resulting in iron overload, oxidative stress, and activation of HSCs into myofibroblasts (70, 74-77).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [70] Remmerie A, Martens L, Thoné T, Castoldi A, Seurinck R, Pavie B, Roels J, Vanneste B, De Prijck S, Vanhockerhout M, Binte Abdul Latib M, Devisscher L, Hoorens A, Bonnardel J, Vandamme N, Kremer A, Borghgraef P, Van Vlierberghe H, Lippens S, Pearce E, Saeys Y, Scott CL, Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver. Immunity 53, 641– 657.e614 (2020). 32888418 PMC7501731 source

      Not checked in the free run.

    • cites [74] Gao H, Jin Z, Bandyopadhyay G, Wang G, Zhang D, Rocha K. C. e., Liu X, Zhao H, Kisseleva T, Brenner DA, Karin M, Ying W, Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metabolism 34, 1201– 1213.e1205 (2022). 35921818 PMC9365100 source

      Not checked in the free run.

    • cites [75] Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gélineau A, Marcelin G, Magréau-Davy E, Ouhachi M, Lesnik P, Boissonnas A, Le Goff W, Clausen BE, Yvan-Charvet L, Sennlaub F, Huby T, Gautier EL, Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis. Immunity 53, 627– 640.e625 (2020). 32562600 source

      Not checked in the free run.

    • cites [76] Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I, Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 178, 686– 698.e614 (2019). 31257031 PMC7068689 source

      Not checked in the free run.

    • cites [77] Seidman JS, Troutman TD, Sakai M, Gola A, Spann NJ, Bennett H, Bruni CM, Ouyang Z, Li RZ, Sun X, Vu BT, Pasillas MP, Ego KM, Gosselin D, Link VM, Chong L-W, Evans RM, Thompson BM, McDonald JG, Hosseini M, Witztum JL, Germain RN, Glass CK, Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis. Immunity 52, 1057– 1074.e1057 (2020). 32362324 PMC7305990 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibiting hedgehog signaling can attenuate HSC activation and MASH fibrosis.

    “Inhibiting hedgehog signaling can attenuate HSC activation and MASH fibrosis (112, 113).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, Tabas I, Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metabolism 24, 848– 862 (2016). 28068223 PMC5226184 source

      Not checked in the free run.

    • cites [113] Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K-L, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I, Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism 31, 969– 986.e967 (2020). 32259482 PMC7313619 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In experimental MASH and human disease, a subset of hepatocytes expressing the Ephrin B2 receptor can induce cell-autonomous inflammation that provokes fibrosis, making these cells a potential therapeutic target.

    “For example, in experimental MASH and human disease a subset of hepatocytes that express the Ephrin B2 receptor can induce cell-autonomous inflammation that provokes fibrosis, establishing these cells as a potential therapeutic target (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactivation of notch signaling in hepatocytes in MASH can increase SPP1 expression, which activates HSCs in a paracrine manner.

    “Reactivation of notch signaling in hepatocytes in MASH can increase SPP1 expression, which activates HSCs in a paracrine manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bulk RNA-seq liver gene signatures from whole liver, isolated hepatocytes, non-parenchymal cells, or plasma correlate with disease features and sometimes predict transition from MASLD to MASH.

    “Through the use of bulk RNA-seq, liver gene signatures were derived from whole liver, isolated hepatocytes, isolated non-parenchymal cells, or plasma that correlated with various disease features and, in some cases, predicted the transition from MASLD to MASH (44, 116-122).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [44] Marcher A-B, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K, Transcriptional regulation of Hepatic Stellate Cell activation in NASH. Sci Rep-Uk 9, 2324 (2019). PMC6382845 30787418 source

      Not checked in the free run.

    • cites [116] Govaere O, Cockell S, Tiniakos D, Queen R, Younes R, Vacca M, Alexander L, Ravaioli F, Palmer J, Petta S, Boursier J, Rosso C, Johnson K, Wonders K, Day CP, Ekstedt M, Orešič M, Darlay R, Cordell HJ, Marra F, Vidal-Puig A, Bedossa P, Schattenberg JM, Clément K, Allison M, Bugianesi E, Ratziu V, Daly AK, Anstee QM, Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Science Translational Medicine 12, eaba4448 (2020). 33268509 source

      Not checked in the free run.

    • cites [117] Vandel J, Dubois-Chevalier J, Gheeraert C, Derudas B, Raverdy V, Thuillier D, Gaal L, Francque S, Pattou F, Staels B, Eeckhoute J, Lefebvre P, Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH). Hepatology 73, 920– 936 (2021). 32394476 PMC8048532 source

      Not checked in the free run.

    • cites [118] Santhekadur PK, Kumar DP, Sanyal AJ, Preclinical models of non-alcoholic fatty liver disease. Journal of Hepatology 68, 230– 237 (2018). 29128391 PMC5775040 source

      Not checked in the free run.

    • cites [119] Cazanave S, Podtelezhnikov A, Jensen K, Seneshaw M, Kumar DP, Min H-K, Santhekadur PK, Banini B, Mauro AG, Oseini AM, Vincent R, Tanis KQ, Webber AL, Wang L, Bedossa P, Mirshahi F, Sanyal AJ, The Transcriptomic Signature Of Disease Development And Progression Of Nonalcoholic Fatty Liver Disease. Sci Rep-Uk 7, 17193 (2017). PMC5722878 29222421 source

      Not checked in the free run.

    • cites [120] Lake AD, Novak P, Fisher CD, Jackson JP, Hardwick RN, Billheimer DD, Klimecki WT, Cherrington NJ, Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease. Drug Metabolism and Disposition 39, 1954 (2011). 21737566 PMC3186211 source

      Not checked in the free run.

    • cites [121] van Koppen A, Verschuren L, van den Hoek AM, Verheij J, Morrison MC, Li K, Nagabukuro H, Costessi A, Caspers MPM, van den Broek TJ, Sagartz J, Kluft C, Beysen C, Emson C, van Gool AJ, Goldschmeding R, Stoop R, Bobeldijk-Pastorova I, Turner SM, Hanauer G, Hanemaaijer R, Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model. Cellular and Molecular Gastroenterology and Hepatology 5, 83– 98.e10 (2018). 29276754 PMC5738456 source

      Not checked in the free run.

    • cites [122] Lefebvre P, Lalloyer F, Baugé E, Pawlak M, Gheeraert C, Dehondt H, Vanhoutte J, Woitrain E, Hennuyer N, Mazuy C, Bobowski-Gérard M, Zummo FP, Derudas B, Driessen A, Hubens G, Vonghia L, Kwanten WJ, Michielsen P, Vanwolleghem T, Eeckhoute J, Verrijken A, Van Gaal L, Francque S, Staels B, Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin. JCI Insight 2, (2017). PMC5499370 28679947 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Notable reactivated hepatocyte pathways include YAP/TAZ, hedgehog, and notch.

    “Notable among these pathways are yes-associated protein 1 (YAP)/tafazzin (TAZ), hedgehog, and, notch, as well as others (111).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Loft A, Alfaro AJ, Schmidt SF, Pedersen FB, Terkelsen MK, Puglia M, Chow KK, Feuchtinger A, Troullinaki M, Maida A, Wolff G, Sakurai M, Berutti R, Ekim Üstünel B, Nawroth P, Ravnskjaer K, Diaz MB, Blagoev B, Herzig S, Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication. Cell Metabolism 33, 1685– 1700.e1689 (2021). 34237252 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although activated HSCs are the primary fibrogenic cells in MASH, single-cell methods have identified an expanded list of fibrogenic drivers expressed by activated HSCs that could be antifibrotic drug targets.

    “Although activated HSCs are the primary fibrogenic cells in MASH, these methods have identified an expanded list of fibrogenic drivers expressed by activated HSCs that could represent antifibrotic drug targets (42, 48, 49, 125).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 source

      Not checked in the free run.

    • cites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source

      Not checked in the free run.

    • cites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

      Not checked in the free run.

    • cites [125] Fred RG, Steen Pedersen J, Thompson JJ, Lee J, Timshel PN, Stender S, Opseth Rygg M, Gluud LL, Bjerregaard Kristiansen V, Bendtsen F, Hansen T, Pers TH, Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis. Sci Rep-Uk 12, 13484 (2022). PMC9355943 35931712 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A subset of hepatocytes expressing annexin A2 preferentially repopulates damaged tissue in acute liver injury, but its relevance to MASH injury is unclear.

    “Conversely, a recent study has identified a subset of hepatocytes that express annexin A2 that preferentially repopulate damaged tissue in acute liver injury (115) – the relevance of this finding to MASH injury is not clear yet.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Matchett KP, Wilson-Kanamori JR, Portman JR, Kapourani CA, Fercoq F, May SB, Mackey JBG, Brice M, Zajdel E, Beltran MS, Sutherland EF, Wilson JC, Wallace SJ, Kitto L, Younger NT, Dobie R, Oniscu GC, Wigmore SJ, Ramachandiran P, Vallejos CA, Carragher NO, Simpson KJ, Kendall TJ, Rule JA, Lee WM, Hoare M, Weston CJ, Marioni JC, Teichmann ST, Bird TG, Carlin LM, Henderson NC, Multimodal decoding of human liver regeneration. bioRxiv, (2023). PMC11153152 38693268 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Some monocyte-derived macrophages resemble Kupffer cells, while others acquire an M2-like polarization and promote inflammation resolution through proresolvin mediators such as maresin 1.

    “Some monocyte-derived macrophages resemble Kupffer cells, the homeostatic liver resident macrophage, whereas others acquire a classical “M2-like” polarization and promote resolution of inflammation through production of proresolvin mediators such as maresin 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LAMs are identified by TREM2, CD9, and SPP1 expression, which also mark scar-associated macrophages in cirrhotic patients, suggesting a common macrophage lineage across liver injury models.

    “LAMs are identified by the expression of TREM2, Tetraspanin CD9 (CD9), and SPP1, which also represent markers of scar-associated macrophages (SAMs) in cirrhotic patients, suggesting a common macrophage lineage in different liver injury models (51).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, Portman JR, Matchett KP, Brice M, Marwick JA, Taylor RS, Efremova M, Vento-Tormo R, Carragher NO, Kendall TJ, Fallowfield JA, Harrison EM, Mole DJ, Wigmore SJ, Newsome PN, Weston CJ, Iredale JP, Tacke F, Pollard JW, Ponting CP, Marioni JC, Teichmann SA, Henderson NC, Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512– 518 (2019). 31597160 PMC6876711 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LSEC activation involves VCAM-1 expression, which recruits pro-inflammatory and pro-fibrogenic immune cells and disrupts the quiescent state of HSCs.

    “This activation involves the expression of adhesion proteins such as vascular cell adhesion molecule 1 (VCAM-1), which directly recruits pro-inflammatory and pro-fibrogenic immune cells into the liver, while also disrupting the quiescent state of HSCs (104) (105-109).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [104] Hammoutene A, Rautou P-E, Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. Journal of Hepatology 70, 1278– 1291 (2019). 30797053 source

      Not checked in the free run.

    • cites [105] DeLeve LD, Wang X, Guo Y, Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920– 930 (2008). 18613151 PMC2695448 source

      Not checked in the free run.

    • cites [106] Xie G, Wang X, Wang L, Wang L, Atkinson RD, Kanel GC, Gaarde WA, DeLeve LD, Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats. Gastroenterology 142, 918– 927.e916 (2012). 22178212 PMC3618963 source

      Not checked in the free run.

    • cites [107] Chen L, Gu T, Li B, Li F, Ma Z, Zhang Q, Cai X, Lu L, Delta-like ligand 4/DLL4 regulates the capillarization of liver sinusoidal endothelial cell and liver fibrogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1866, 1663– 1675 (2019). 31233801 source

      Not checked in the free run.

    • cites [108] Furuta K, Guo Q, Pavelko KD, Lee J-H, Robertson KD, Nakao Y, Melek J, Shah VH, Hirsova P, Ibrahim SH, Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. The Journal of Clinical Investigation 131, (2021). PMC7954604 33476308 source

      Not checked in the free run.

    • cites [109] Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion A-C, Mérian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou P-E, A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. Journal of Hepatology 72, 528– 538 (2020). 31726115 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Single-cell RNA-seq has enabled attribution of differentially expressed genes to specific cell types.

    “Single-cell RNA-seq has enabled researchers to attribute differentially expressed genes to specific cell types.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Seminal work from the Henderson group first profiled hepatic cells, including HSCs from fibrotic mouse and patient livers, and this has since been expanded to MASH by several groups including ours.

    “Seminal work from the Henderson group first profiled hepatic cells, including HSCs from fibrotic mouse and patient livers (50, 51), which has since been expanded to MASH by several other groups including ours.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Dobie R, Wilson-Kanamori JR, Henderson BEP, Smith JR, Matchett KP, Portman JR, Wallenborg K, Picelli S, Zagorska A, Pendem SV, Hudson TE, Wu MM, Budas GR, Breckenridge DG, Harrison EM, Mole DJ, Wigmore SJ, Ramachandran P, Ponting CP, Teichmann SA, Marioni JC, Henderson NC, Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis. Cell Reports 29, 1832– 1847.e1838 (2019). 31722201 PMC6856722 source

      Not checked in the free run.

    • cites [51] Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, Portman JR, Matchett KP, Brice M, Marwick JA, Taylor RS, Efremova M, Vento-Tormo R, Carragher NO, Kendall TJ, Fallowfield JA, Harrison EM, Mole DJ, Wigmore SJ, Newsome PN, Weston CJ, Iredale JP, Tacke F, Pollard JW, Ponting CP, Marioni JC, Teichmann SA, Henderson NC, Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512– 518 (2019). 31597160 PMC6876711 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The liver microenvironment influences monocyte-derived macrophage differentiation, producing several subsets based on gene expression.

    “This process is influenced by the liver microenvironment (101), leading to the identification of several different subsets of monocyte-derived macrophages based on their gene expression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Lavin Y, Mortha A, Rahman A, Merad M, Regulation of macrophage development and function in peripheral tissues. Nature Reviews Immunology 15, 731– 744 (2015). PMC4706379 26603899 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In MASH, liver sinusoidal endothelial cells lose fenestration, have fewer autophagic vacuoles, and acquire an activated phenotype.

    “In MASH, liver sinusoidal endothelial cells (LSECs) undergo a morphological transition characterized by the loss of fenestration, lower prevalence of autophagic vacuoles, and the acquisition of an”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent study implicates TGFβ2 and TGFβ3 as potent fibrogenic stimuli that lack the pro-inflammatory effects of TGFβ1 antagonism.

    “Although studies have long implicated TGFβ1 as the dominant fibrogenic driver, a recent study also implicates TGFβ2 and TGFβ3 as potent fibrogenic stimuli, but which lack the pro-inflammatory effects of TGFβ1 antagonism that have limited the latter’s appeal as a therapeutic target (147).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Sun T, Huang Z, Liang WC, Yin J, Lin WY, Wu J, Vernes JM, Lutman J, Caplazi P, Jeet S, Wong T, Wong M, DePianto DJ, Morshead KB, Sun KH, Modrusan Z, Vander Heiden JA, Abbas AR, Zhang H, Xu M, N'Diaye EN, Roose-Girma M, Wolters PJ, Yadav R, Sukumaran S, Ghilardi N, Corpuz R, Emson C, Meng YG, Ramalingam TR, Lupardus P, Brightbill HD, Seshasayee D, Wu Y, Arron JR, TGFbeta2 and TGFbeta3 isoforms drive fibrotic disease pathogenesis. Sci Transl Med 13, (2021). 34349032 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These genetic findings may explain the overrepresentation of Hispanic individuals and underrepresentation of African Americans in MASH clinics.

    “These findings may explain the overrepresentation of Hispanic and underrepresentation of African Americans in MASH clinics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Few genetic variants have been mechanistically linked to MASH pathogenesis, and each has only a modest population-level effect, suggesting environmental determinants are more important in driving disease.

    “Although these findings provide valuable insights into the mechanisms underlying MASH, overall, few genetic variants have been mechanistically linked to MASH pathogenesis (145), and each exerts only a modest effect on disease outcome at the population level, suggesting that environmental determinants play a more important role in driving the disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers RP, Schneider CV, Park J, Lee KM, Serper M, Carr RM, Kaplan DE, Haas ME, MacLean MT, Witschey WR, Zhu X, Tcheandjieu C, Kember RL, Kranzler HR, Verma A, Giri A, Klarin DM, Sun YV, Huang J, Huffman JE, Creasy KT, Hand NJ, Liu CT, Long MT, Yao J, Budoff M, Tan J, Li X, Lin HJ, Chen YI, Taylor KD, Chang RK, Krauss RM, Vilarinho S, Brancale J, Nielsen JB, Locke AE, Jones MB, Verweij N, Baras A, Reddy KR, Neuschwander-Tetri BA, Schwimmer JB, Sanyal AJ, Chalasani N, Ryan KA, Mitchell BD, Gill D, Wells AD, Ma source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Absence of HSD17B13 protein due to a truncation variant is protective against fibrosis, suggesting the enzyme generates a lipotoxic species absent in variant carriers, but the native substrate and product are not established.

    “Absence of the HSD17B13 protein due to a truncation variant is protective against fibrosis, suggesting that this enzyme generates a potential lipotoxic species, which is absent from those with the variant, however the native substrate and product of this protein have not been established.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The HSD17B13 splice variant rs72613567 is protective against MASH, and HSD17B13 may contribute to MASH fibrosis by promoting pyrimidine catabolism.

    “Furthermore, the splice variant rs72613567 in the Hydroxysteroid 17-beta Dehydrogenase 13 (HSD17B13) gene has been identified as protective against MASH, with HSD17B13 potentially contributing to MASH fibrosis by promoting pyrimidine catabolism (134, 140-142).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source

      Not checked in the free run.

    • cites [140] Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, Allison MED, Alexander GJ, Piguet A-C, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour J-F, Day CP, Daly AK, Anstee QM, TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 5, 4309 (2014). PMC4279183 24978903 source

      Not checked in the free run.

    • cites [141] Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Kärjä V, Borén J, Käkelä P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamäki J, Fargion S, Sjöström L, Carlsson LM, Romeo S, Valenti L, Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506– 514 (2015). 25251399 source

      Not checked in the free run.

    • cites [142] Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC, Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 46, 352– 356 (2014). 24531328 PMC3969786 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The TM6SF2 rs58542926 minor allele is reportedly associated with MASLD and sometimes MASH.

    “The rs58542926 minor allele of transmembrane 6 superfamily member 2 (TM6SF2) is also reportedly associated with MASLD and sometimes MASH (134, 140-142).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source

      Not checked in the free run.

    • cites [140] Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, Allison MED, Alexander GJ, Piguet A-C, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour J-F, Day CP, Daly AK, Anstee QM, TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 5, 4309 (2014). PMC4279183 24978903 source

      Not checked in the free run.

    • cites [141] Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Kärjä V, Borén J, Käkelä P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamäki J, Fargion S, Sjöström L, Carlsson LM, Romeo S, Valenti L, Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506– 514 (2015). 25251399 source

      Not checked in the free run.

    • cites [142] Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC, Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 46, 352– 356 (2014). 24531328 PMC3969786 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron shuttled by extracellular vesicles from hepatocytes to HSCs in MASH stimulates fibrogenesis through iron overload and oxidative stress, exacerbated by TGFβ-mediated suppression of cytoglobin.

    “Iron can be shuttled by extracellular vesicles from hepatocytes to HSCs in MASH, stimulating fibrogenesis through iron overload and oxidative stress, an effect that is further exacerbated by TGFβ-mediated suppression of the antioxidant protein cytoglobin (CYGB) (74) (149).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Gao H, Jin Z, Bandyopadhyay G, Wang G, Zhang D, Rocha K. C. e., Liu X, Zhao H, Kisseleva T, Brenner DA, Karin M, Ying W, Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metabolism 34, 1201– 1213.e1205 (2022). 35921818 PMC9365100 source

      Not checked in the free run.

    • cites [149] Okina Y, Sato-Matsubara M, Matsubara T, Daikoku A, Longato L, Rombouts K, Thanh Thuy LT, Ichikawa H, Minamiyama Y, Kadota M, Fujii H, Enomoto M, Ikeda K, Yoshizato K, Pinzani M, Kawada N, TGF-β1-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis. Journal of Hepatology 73, 882– 895 (2020). 32330605 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PNPLA3 rs738409[G] (I148M) carriers are most prevalent in Hispanics and have increased susceptibility to MASLD and MASH.

    “Among these polymorphisms, carriers of the Patatin Like Phospholipase Domain Containing 3 (PNPLA3) allele rs738409[G] (encoding I148M) are most prevalent in Hispanics and display an increased susceptibility to MASLD and MASH.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH, Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 40, 1461– 1465 (2008). 18820647 PMC2597056 source

      Not checked in the free run.

    • cites [133] Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, Nobili V, Mozzi E, Roviaro G, Vanni E, Bugianesi E, Maggioni M, Fracanzani AL, Fargion S, Day CP, Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209– 1217 (2010). 20373368 source

      Not checked in the free run.

    • cites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Single-cell studies have revealed heterogeneity within cell types in health and disease, identifying multiple HSC clusters in murine MASH fibrosis and human cirrhosis.

    “Single-cell studies have also revealed remarkable heterogeneity within different cell types in health and disease, identifying multiple HSC clusters in murine models of MASH fibrosis and human cirrhosis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 source

      Not checked in the free run.

    • cites [99] Payen VL, Lavergne A, Alevra Sarika N, Colonval M, Karim L, Deckers M, Najimi M, Coppieters W, Charloteaux B, Sokal EM, El Taghdouini A, Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep 3, 100278 (2021). 34027339 PMC8121977 source

      Not checked in the free run.

    • cites [126] Carter J, Wang S, Friedman SL, Ten Thousand Points of Light: Heterogeneity Among the Stars of NASH Fibrosis. Hepatology 74, (2021). PMC8390430 33724489 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Differential ligand-receptor signaling pairs suggest that disease drivers and signaling events may change as disease advances, so advanced fibrotic stages may respond to different pharmacotherapies than earlier stages.

    “These different communication networks are reflected in the differential expression of ligand-receptor signaling pairs, suggesting that the repertoire of disease drivers – and therefore the underlying signaling events – may change as the disease advances, such that advanced fibrotic stages may respond to different pharmacotherapies than earlier stages (48, 49).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source

      Not checked in the free run.

    • cites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High cholesterol and free cholesterol accumulation in HSCs in MCD MASH mice increases TLR4 and sensitizes the cells to TGFβ-induced activation.

    “High concentrations of cholesterol and free cholesterol accumulate in HSCs in methionine-choline deficient (MCD) MASH mice, which increases toll-like receptor 4 (TLR4) and sensitizes the cells to TGFβ–induced activation (148).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Okada Y, Kurihara C, Irie R, Yokoyama H, Shimamura K, Usui S, Ebinuma H, Saito H, Watanabe C, Komoto S, Kawaguchi A, Nagao S, Sugiyama K, Hokari R, Kanai T, Miura S, Hibi T, Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154– 169 (2014). 23832448 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisereasoning

    HSD17B13 is not expressed by HSCs, indicating that its effect on fibrosis is indirect and mediated by changes in hepatocytes.

    “Furthermore, HSD17B13 is not expressed by HSCs, indicating that the impact of the gene in promoting or protecting from fibrosis is indirect and due to changes in hepatocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The I148M SNP drives injury and fibrosis by promoting fat accumulation in hepatocytes and enhancing HSC fibrogenic activity.

    “From a mechanistic perspective, the I148M single nucleotide polymorphism (SNP) drives injury and fibrosis by promoting fat accumulation in hepatocytes (135) and enhancing fibrogenic activity of HSCs (136), respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] BasuRay S, Smagris E, Cohen JC, Hobbs HH, The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111– 1124 (2017). 28520213 PMC5605398 source

      Not checked in the free run.

    • cites [136] Bruschi FV, Claudel T, Tardelli M, Caligiuri A, Stulnig TM, Marra F, Trauner M, The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65, 1875– 1890 (2017). 28073161 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA methylation patterns at fibrosis-related genes such as TGFβ1, COL1A1, PDGFα, PPARα, and PPARδ can distinguish mild from advanced MASLD and predict future fibrosis progression.

    “Moreover, certain patterns of DNA methylation at fibrosis-related genes, such as those encoding TGFβ1, COL1A1, PDGFα, peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferator-activated receptor delta (PPARδ), can not only distinguish between patients with mild versus advanced MASLD, but also predict future fibrosis progression (169-172).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [169] Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, Garrett ME, Ashley–Koch A, Suzuki A, Tillmann HL, Hauser MA, Diehl AM, Relationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 145, 1076– 1087 (2013). 23916847 PMC3805742 source

      Not checked in the free run.

    • cites [170] Hardy T, Zeybel M, Day CP, Dipper C, Masson S, McPherson S, Henderson E, Tiniakos D, White S, French J, Mann DA, Anstee QM, Mann J, Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 66, 1321 (2017). 27002005 PMC5031527 source

      Not checked in the free run.

    • cites [171] Zeybel M, Hardy T, Robinson SM, Fox C, Anstee QM, Ness T, Masson S, Mathers JC, French J, White S, Mann J, Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clinical Epigenetics 7, 25 (2015). 25859289 PMC4391139 source

      Not checked in the free run.

    • cites [172] Johnson ND, Wu X, Still CD, Chu X, Petrick AT, Gerhard GS, Conneely KN, DiStefano JK, Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clinical Epigenetics 13, 152 (2021). 34353365 PMC8340447 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BMP8B is upregulated in MASH and signals through SMADs to drive HSC activation in animal models.

    “Another ligand of the TGFβ-bone morphogenetic protein (BMP) superfamily, bone morphogenetic protein 8B (BMP8B), is upregulated in MASH and signals through mothers against decapentaplegic (SMADs) to drive HSC activation in animal models, reinforcing TGFβ's vital role as a fibrogenic stimulus (150).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Vacca M, Leslie J, Virtue S, Lam BYH, Govaere O, Tiniakos D, Snow S, Davies S, Petkevicius K, Tong Z, Peirce V, Nielsen MJ, Ament Z, Li W, Kostrzewski T, Leeming DJ, Ratziu V, Allison MED, Anstee QM, Griffin JL, Oakley F, Vidal-Puig A, Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis. Nature Metabolism 2, 514– 531 (2020). PMC7617436 32694734 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    Genetic depletion of Indian hedgehog from hepatocytes reduces MASH fibrosis and hepatocellular carcinoma in a dietary mouse model, suggesting different hedgehog ligands may have distinct activities.

    “On the other hand, genetic depletion of Indian hedgehog from hepatocytes reduces MASH fibrosis and hepatocellular carcinoma in a dietary mouse model, suggesting that different hedgehog ligands may have distinct activities (158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Chong YC, Lim TE, Fu Y, Shin EM, Tergaonkar V, Han W, Indian Hedgehog links obesity to development of hepatocellular carcinoma. Oncogene 38, 2206– 2222 (2019). 30470823 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    HSCs synthesize hyaluronic acid via HAS2, which promotes fibrogenicity in a NOTCH1-dependent manner by stimulating TLR4 and CD44 on HSCs.

    “Furthermore, HSCs synthesize hyaluronic acid through the expression of hyaluronic acid synthase 2, which promotes fibrogenicity in a NOTCH1-dependent manner by stimulating TLR4 and CD44 expressed on HSCs themselves (154).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Yang YM, Noureddin M, Liu C, Ohashi K, Kim SY, Ramnath D, Powell EE, Sweet MJ, Roh YS, Hsin IF, Deng N, Liu Z, Liang J, Mena E, Shouhed D, Schwabe RF, Jiang D, Lu SC, Noble PW, Seki E, Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci Transl Med 11, (2019). PMC6589184 31189722 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hepatocytes, TLR4 activation increases JAG1, leading to SOX9-dependent transcription and SPP1 secretion, which stimulates HSC activation.

    “In hepatocytes, activation of TLR4 increases the expression of jagged 1 (JAG1), a well-established notch receptor 1 (NOTCH1) ligand, which leads to SRY-box transcription factor 9 (SOX9)-dependent transcription and secretion of SPP1, stimulating HSC activation (114).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Zhu C, Kim K, Wang X, Bartolome A, Salomao M, Dongiovanni P, Meroni M, Graham MJ, Yates KP, Diehl AM, Schwabe RF, Tabas I, Valenti L, Lavine JE, Pajvani UB, Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 10, eaat0344 (2018). 30463916 PMC6822168 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Epigenetic regulation plays a critical role in conveying environmental information that influences gene expression and cellular behavior.

    “Epigenetic regulation plays a critical role in conveying environmental information that influences gene expression and cellular behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NOTCH expression is detected in endothelial cells of MASH patients, and selective depletion or overexpression reduces or aggravates MASH fibrosis in murine models, possibly by modulating eNOS.

    “NOTCH expression has also been detected in endothelial cells of patients with MASH, and its selective depletion or overexpression can reduce or aggravate MASH fibrosis in murine models, respectively, possibly by modulating nitric oxide synthase 3 (eNOS) (155).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Fang Z-Q, Ruan B, Liu J-J, Duan J-L, Yue Z-S, Song P, Xu H, Ding J, Xu C, Dou G-R, Wang L, Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through endothelial nitric oxide synthase. Hepatology 76, 742– 758 (2022). 35006626 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model.

    “SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model (38, 159).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Syn W-K, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM, Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, 106– 115 (2011). 20967826 PMC3025083 source

      Not checked in the free run.

    • cites [159] Sahai A, Malladi P, Melin-Aldana H, Green RM, Whitington PF, Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol-Gastr L 287, G264– G273 (2004). 15044174 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    SPP1 expression and secretion are promoted by NFATc4 and CHCHD2, transcription factors activated in MASH mice and patients.

    “SPP1 expression and secretion is also promoted by nuclear factor of activated T cells 4 (NFATc4) and coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), transcription factors activated in MASH mice and patients (160, 161).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [160] Du M, Wang X, Yuan L, Liu B, Mao X, Huang D, Yang L, Huang K, Zhang F, Wang Y, Luo X, Wang C, Peng J, Liang M, Huang D, Huang K, Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice. Journal of Hepatology 73, 1333– 1346 (2020). 32717288 source

      Not checked in the free run.

    • cites [161] Li Y, Xiu W, Xu J, Chen X, Wang G, Duan J, Sun L, Liu B, Xie W, Pu G, Wang Q, Wang C, Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch/osteopontin signaling. JCI Insight 7, (2022). PMC9746920 36477358 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Hepatocyte ballooning is a prominent pathologic hallmark that distinguishes MASH from MASLD and is thought to represent a unique injury associated with lipotoxicity and release of inflammatory and fibrogenic signals.

    “Ballooning of hepatocytes is a prominent pathologic hallmark of MASH that distinguishes MASH from MASLD and is thought to represent a unique type of cell injury that is associated with lipotoxicity and release of inflammatory and fibrogenic signals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other major sources of hedgehog ligands may be reactive-appearing ductular cells that correlate with fibrosis in MASH patients, or MASH-associated hepatocytes in which increased cholesterol activates TAZ to drive Indian hedgehog expression and secretion.

    “Other major sources of hedgehog ligands may be reactive-appearing ductular cells that strongly correlate with fibrosis in patients with MASH or in MASH-associated hepatocytes where increased cholesterol intake activate TAZ to drive Indian hedgehog expression and secretion (112, 113, 163).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [112] Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, Tabas I, Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metabolism 24, 848– 862 (2016). 28068223 PMC5226184 source

      Not checked in the free run.

    • cites [113] Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K-L, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I, Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism 31, 969– 986.e967 (2020). 32259482 PMC7313619 source

      Not checked in the free run.

    • cites [163] Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H, Diehl AM, Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. Journal of Hepatology 63, 962– 970 (2015). 26070409 PMC4575842 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSC activation requires energy and relies on autophagy to release fatty acids through hydrolysis of retinyl esters, linked to endoplasmic reticulum stress.

    “In addition to generation of intermediary metabolites through glycolysis, lipolysis, and glutaminolysis, the cells rely on activation of autophagy to release fatty acids through hydrolysis of retinyl esters (183) linked to endoplasmic reticulum stress (184).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [183] Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, Gordon R, Fiel MI, Yue Z, Czaja MJ, Friedman SL, Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938– 946 (2012). 22240484 PMC3439519 source

      Not checked in the free run.

    • cites [184] Hernandez-Gea V, Hilscher M, Rozenfeld R, Lim MP, Nieto N, Werner S, Devi LA, Friedman SL, Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 59, 98– 104 (2013). 23485523 PMC3686909 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipoprotein lipase promotes free cholesterol accumulation in HSCs, activating TLR4 signaling and reducing Bambi expression, which together sensitize HSCs to TGFβ-driven activation.

    “Mechanistically, lipoprotein lipase promotes free cholesterol accumulation in HSCs, which in turn activates TLR4 signaling and reduces Bambi expression that together sensitizes HSCs to TGFβ-driven activation (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T, Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. Hepatology Communications 3, 1098– 1112 (2019). 31388630 PMC6671781 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    For MASH, only cholesterol and lipid metabolism have been linked to HSC fibrogenicity in vivo.

    “However, for MASH, only cholesterol and lipid metabolism have been linked to HSC fibrogenicity in vivo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Fecal transplant studies have yielded mixed results, and no single bacterium has emerged as a pathogenic agent across different studies.

    “These findings implicate the microbiota in driving this critical transition, but fecal transplant studies have yielded mixed results and no single bacterium has emerged as a pathogenic agent across different studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Transplant of fecal microbiota from lean healthy donors into obese patients improved lipid profiles and reduced liver stiffness in one study.

    “Transplant of fecal microbiota from lean healthy donors into obese patients improved lipid profiles and reduced liver stiffness in one study (200), whereas in another a synbiotic formation (probiotics + prebiotics) failed to alter fibrosis (201).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Ng SC, Xu Z, Mak JWY, Yang K, Liu Q, Zuo T, Tang W, Lau L, Lui RN, Wong SH, Tse YK, Li AYL, Cheung K, Ching JYL, Wong VWS, Kong APS, Ma RCW, Chow EYK, Wong SKH, Ho ICH, Chan PKS, Chan FKL, Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial. Gut 71, 716 (2022). 33785557 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies in different mouse strains show that plasma cholesterol strongly correlates with fibrosis extent, and high-cholesterol supplementation increases fibrosis.

    “Studies on different strains of mice have shown that plasma cholesterol strongly correlates with the extent of fibrosis, and mice supplemented with high cholesterol develop increased fibrosis (148, 186).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Okada Y, Kurihara C, Irie R, Yokoyama H, Shimamura K, Usui S, Ebinuma H, Saito H, Watanabe C, Komoto S, Kawaguchi A, Nagao S, Sugiyama K, Hokari R, Kanai T, Miura S, Hibi T, Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154– 169 (2014). 23832448 source

      Not checked in the free run.

    • cites [186] Hui ST, Kurt Z, Tuominen I, Norheim F, Davis RC, Pan C, Dirks DL, Magyar CE, French SW, Chella Krishnan K, Sabir S, Campos-Pérez F, Méndez-Sánchez N, Macías-Kauffer L, León-Mimila P, Canizales-Quinteros S, Yang X, Beaven SW, Huertas-Vazquez A, Lusis AJ, The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68, (2018). PMC6269199 29907965 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    Co-housing wildtype mice with MASH-prone mice increased disease severity in wildtype mice, presumably due to transfer of fecal microbiota.

    “Co-housing wildtype mice with mice prone to MASH led to increased disease severity in wildtype mice, presumably due to a transfer of fecal microbiota (204).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez J-P, Shulman GI, Gordon JI, Hoffman HM, Flavell RA, Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179– 185 (2012). 22297845 PMC3276682 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipoprotein lipase abundance increases in HSCs in MASLD and MASH patients, and selective depletion in HSCs reduces activation and fibrosis progression in a rodent MASLD model.

    “Lipoprotein lipase abundance also increases in HSCs in patients with MASLD and MASH, and depletion of lipoprotein lipase selectively in HSCs reduces their activation and liver fibrosis progression in a rodent model of MASLD (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T, Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. Hepatology Communications 3, 1098– 1112 (2019). 31388630 PMC6671781 source

      Not checked in the free run.

    • Rests on an assumption: Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

  • May combine two claims.

    Premisecitation

    Autophagy provokes release of miR-29a, which can stimulate fibrogenesis in neighboring cells through paracrine signaling.

    “Autophagy also provokes the release of miR-29a, which can stimulate fibrogenesis in neighboring cells through paracrine signaling (185).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Yu X, Elfimova N, Muller M, Bachurski D, Koitzsch U, Drebber U, Mahabir E, Hansen HP, Friedman SL, Klein S, Dienes HP, Hosel M, Buettner R, Trebicka J, Kondylis V, Mannaerts I, Odenthal M, Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cell Mol Gastroenterol Hepatol 13, 1701– 1716 (2022). 35219894 PMC9046234 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice overexpressing both ACC1 and ACC2 show increased hepatic de novo lipogenesis and spontaneously develop MASH-like symptoms.

    “Mice overexpressing both ACC1 and ACC2 display increased de novo lipogenesis in the liver and spontaneously develop MASH-like symptoms (189).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen Z-P, O'Neill HM, Ford RJ, Palanivel R, O'Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JRB, van Denderen BJ, Kemp BE, Steinberg GR, Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine 19, 1649– 1654 (2013). PMC4965268 24185692 source

      Not checked in the free run.

    • Rests on an assumption: ACC is the rate-limiting enzyme in de novo lipogenesis.

  • May combine two claims.

    Premisereasoning

    MCD mice do not become obese and fail to develop associated metabolic defects, including insulin resistance.

    “However, these mice do not become obese and therefore fail to develop associated metabolic defects, including insulin resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A study in approximately 100 common inbred mouse strains expressing human APOE*3-Leiden and cholesteryl ester transfer protein revealed a wide spectrum of fibrosis development, from non-detectable to robust, indicating a major contribution of genetic background to MASH pathology.

    “The degree of fibrosis ranged from non-detectable to robust, indicating a major contribution of genetic background to MASH pathology (186).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Hui ST, Kurt Z, Tuominen I, Norheim F, Davis RC, Pan C, Dirks DL, Magyar CE, French SW, Chella Krishnan K, Sabir S, Campos-Pérez F, Méndez-Sánchez N, Macías-Kauffer L, León-Mimila P, Canizales-Quinteros S, Yang X, Beaven SW, Huertas-Vazquez A, Lusis AJ, The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68, (2018). PMC6269199 29907965 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Oz mouse harbors a spontaneous Alms1 mutation similar to Alstrom syndrome; combined with a Western diet on a C57BL/6 background, it leads to obesity and diabetes, then MASH with advanced fibrosis by 12 weeks of age.

    “The Oz mouse harbors a spontaneous mutation within the Alstrom syndrome 1 (Alms1) gene, similar to patients with Alstrom syndrome, which, when combined with a Western diet on a C57BL/6 background, leads to obesity and diabetes, then MASH, with advanced fibrosis by 12 weeks of age (43, 229, 230).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Ganguly S, Muench GA, Shang L, Rosenthal SB, Rahman G, Wang R, Wang Y, Kwon HC, Diomino AM, Kisseleva T, Soorosh P, Hosseini M, Knight R, Schnabl B, Brenner DA, Dhar D, Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet. Cellular and Molecular Gastroenterology and Hepatology 12, 891– 920 (2021). 34062281 PMC8342972 source

      Not checked in the free run.

    • cites [229] Farrell GC, Mridha AR, Yeh MM, Arsov T, Van Rooyen DM, Brooling J, Nguyen T, Heydet D, Delghingaro-Augusto V, Nolan CJ, Shackel NA, McLennan SV, Teoh NC, Larter CZ, Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver International 34, 1084– 1093 (2014). 24107103 source

      Not checked in the free run.

    • cites [230] Arsov T, Silva DG, O’Bryan MK, Sainsbury A, Lee NJ, Kennedy C, Manji SSM, Nelms K, Liu C, Vinuesa CG, de Kretser DM, Goodnow CC, Petrovsky N, Fat Aussie—A New Alström Syndrome Mouse Showing a Critical Role for ALMS1 in Obesity, Diabetes, and Spermatogenesis. Molecular Endocrinology 20, 1610– 1622 (2006). 16513793 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adiponectin has antifibrotic properties but has not yet emerged as a therapeutic.

    “A different adipocyte secreted hormone, adiponectin, has antifibrotic properties but has not yet emerged as a therapeutic, although increased adiponectin is emerging as an indication of therapeutic benefit in clinical trials of metabolic therapy for MASH (220).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso A, Jimenez-Aguero R, Eizaguirre E, Bujanda L, Pareja MJ, Luis R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP, Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 8, 683250 (2021). 34249975 PMC8260936 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rodent models of MASH comprise three broad categories: diet-based, genetic, and mixed.

    “Rodent models of MASH have been extensively reviewed and comprise 3 broad categories: 1) diet-based; 2) genetic; or 3) mixed, which refers to combined diet, genetic, or chemical perturbations (118, 210-213).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [118] Santhekadur PK, Kumar DP, Sanyal AJ, Preclinical models of non-alcoholic fatty liver disease. Journal of Hepatology 68, 230– 237 (2018). 29128391 PMC5775040 source

      Not checked in the free run.

    • cites [210] Hunter H, de Gracia Hahn D, Duret A, Im YR, Cheah Q, Dong J, Fairey M, Hjalmarsson C, Li A, Lim HK, McKeown L, Mitrofan C-G, Rao R, Utukuri M, Rowe IA, Mann JP, Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver. eLife 9, e56573 (2020). 33063664 PMC7647398 source

      Not checked in the free run.

    • cites [211] Ibrahim SH, Hirsova P, Malhi H, Gores GJ, Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. Digest Dis Sci 61, 1325– 1336 (2016). 26626909 PMC4838538 source

      Not checked in the free run.

    • cites [212] Brenner DA, Of Mice and Men and Nonalcoholic Steatohepatitis. Hepatology 68, 2059– 2061 (2018). 30033687 PMC6398944 source

      Not checked in the free run.

    • cites [213] Im YR, Hunter H, de Gracia Hahn D, Duret A, Cheah Q, Dong J, Fairey M, Hjalmarsson C, Li A, Lim HK, McKeown L, Mitrofan C-G, Rao R, Utukuri M, Rowe IA, Mann JP, A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD. Hepatology 74, 1884– 1901 (2021). 33973269 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Up to 75% of type II diabetes patients also develop MASLD.

    “The prevalence of co-morbid diabetes and MASH is high, with up to 75% of type II diabetes patients also developing MASLD (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MASH dysbiosis incorporates an altered fungal flora, and antifungals have some efficacy in reducing disease severity and fibrosis in germ-free mice.

    “MASH dysbiosis also incorporates an altered fungal flora, with some efficacy of antifungals in reducing disease severity and fibrosis in germ-free mice (209).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Demir M, Lang S, Hartmann P, Duan Y, Martin A, Miyamoto Y, Bondareva M, Zhang X, Wang Y, Kasper P, Bang C, Roderburg C, Tacke F, Steffen H-M, Goeser T, Kruglov A, Eckmann L, Stärkel P, Fouts DE, Schnabl B, The fecal mycobiome in non-alcoholic fatty liver disease☆. Journal of Hepatology 76, 788– 799 (2022). 34896404 PMC8981795 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Both Oz and Agouti yellow mice follow the natural history of disease progression but require specific genetic backgrounds.

    “Although MASH development in both Oz and Agouti yellow mice follow the natural history of disease progression in humans, both models require mice with specific genetic backgrounds.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Among the most often used genetic models of MASLD are mice deficient for leptin (ob/ob) or the leptin receptor (db/db).

    “Among the most often used genetic models of MASLD are mice genetically deficient for leptin (ob/ob) or the leptin receptor (db/db) (216-219).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [216] Polyzos SA, Kountouras J, Mantzoros CS, Leptin in nonalcoholic fatty liver disease: A narrative review. Metabolism 64, 60– 78 (2015). 25456097 source

      Not checked in the free run.

    • cites [217] Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM, Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene. Science 269, 543– 546 (1995). 7624777 source

      Not checked in the free run.

    • cites [218] Hummel KP, Dickie MM, Coleman DL, Diabetes, a New Mutation in the Mouse. Science 153, 1127– 1128 (1966). 5918576 source

      Not checked in the free run.

    • cites [219] Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF, Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol-Gastr L 287, G1035– G1043 (2004). 15256362 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Liver disease progression is slow on a Western diet alone in common inbred mouse strains such as C57Bl/6, so additional injury may accelerate progression, which can be accomplished by low weekly doses of CCl4.

    “However, liver disease progression is slow on a Western diet alone in common inbred mouse strains such as C57Bl/6 and thus additional injury may accelerate progression, which can be accomplished by administering low weekly doses of the hepatotoxin carbon tetrachloride (CCl4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The DIAMOND mouse model exposes B6/129 mixed strain mice to a Western diet and leads to hepatocellular carcinoma in most animals between 32 and 52 weeks.

    “For instance, the diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) mouse model exposes B6/129 mixed strain mice to a Western diet, leading to the development of hepatocellular carcinoma in most animals between 32-52 weeks (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, Kumar DP, Daita K, Min H-K, Mirshahi F, Bedossa P, Sun X, Hoshida Y, Koduru SV, Contaifer D, Warncke UO, Wijesinghe DS, Sanyal AJ, A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. Journal of Hepatology 65, 579– 588 (2016). 27261415 PMC5012902 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Earlier stages of MASH fibrosis can regress more easily than advanced stages, a trend observed in other liver diseases.

    “Earlier stages of MASH fibrosis can regress more easily than advanced stages, a trend observed in other liver diseases (260), which may be explained in part by the marked increase in total collagen and extracellular matrix associated with progressive fibrosis (261).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [260] Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R, Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies. Clinical Gastroenterology and Hepatology 13, 643– 654.e649 (2015). 24768810 PMC4208976 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    MASH fibrosis is reversible in non-cirrhotic liver, but there is no evidence yet that cirrhosis in MASH is reversible.

    “Nevertheless, these interventions suggest that, like HCV and HBV, MASH fibrosis is reversible in non-cirrhotic liver, but unlike in HCV and HBV there is no evidence yet that cirrhosis in MASH is reversible (259).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, Ningarhari M, Louvet A, Leteurtre E, Raverdy V, Dharancy S, Pattou F, Mathurin P, Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology 159, 1290– 1301 e1295 (2020). 32553765 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    PCLS requires continued access to human liver core biopsies, which can be challenging to acquire.

    “However, PCLS requires continued access to human liver core biopsies, which can be challenging to acquire.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PCLS cultures are approximately 200 micron-thick tissue slices from liver core biopsy that maintain cell identity and tissue structure for several days under specialized conditions.

    “As a perhaps simpler alternative to organ-on-chip systems, PCLS cultures are ~200 micron-thick tissue slices cut out of a liver core biopsy that has been shown to maintain cell identity and tissue structure for several days when cultured under specialized conditions (248)(249).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [248] van de Bovenkamp M, Groothuis GM, Meijer DK, Olinga P, Precision-cut fibrotic rat liver slices as a new model to test the effects of anti-fibrotic drugs in vitro. J Hepatol 45, 696– 703 (2006). 16828918 source

      Not checked in the free run.

    • cites [249] Paish HL, Reed LH, Brown H, Bryan MC, Govaere O, Leslie J, Barksby BS, Garcia Macia M, Watson A, Xu X, Zaki MYW, Greaves L, Whitehall J, French J, White SA, Manas DM, Robinson SM, Spoletini G, Griffiths C, Mann DA, Borthwick LA, Drinnan MJ, Mann J, Oakley F, A Bioreactor Technology for Modeling Fibrosis in Human and Rodent Precision-Cut Liver Slices. Hepatology, (2019). PMC6852483 30963615 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The microbiome can profoundly influence responsiveness to pharmacotherapies in disease models outside the liver.

    “The microbiome can profoundly influence responsiveness to pharmacotherapies in disease models outside the liver (237, 238), and similar approaches are being explored in MASH.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [237] Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, Hickman HD, McCulloch JA, Badger JH, Ajami NJ, Trinchieri G, Pardo-Manuel de Villena F, Yewdell JW, Rehermann B, Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171, 1015– 1028.e1013 (2017). 29056339 PMC6887100 source

      Not checked in the free run.

    • cites [238] Rosshart SP, Herz J, Vassallo BG, Hunter A, Wall MK, Badger JH, McCulloch JA, Anastasakis DG, Sarshad AA, Leonardi I, Collins N, Blatter JA, Han S-J, Tamoutounour S, Potapova S, Foster St. Claire MB, Yuan W, Sen SK, Dreier MS, Hild B, Hafner M, Wang D, Iliev ID, Belkaid Y, Trinchieri G, Rehermann B, Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaw4361 (2019). 31371577 PMC7377314 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with MASLD may have spontaneous improvement without intervention, which could contribute to high placebo response rates in clinical trials.

    “Additionally patients may have spontaneous improvement without intervention, a feature that could contribute to the surprisingly high rates of response among placebo patients in clinical trials (250-252).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [250] Shamseddeen H, Vilar-Gomez E, Chalasani N, Myers RP, Subramanian GM, Shlevin HH, Allgood AE, Orman ES, Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring. Drug Saf 43, 281– 290 (2020). 31907854 PMC7050367 source

      Not checked in the free run.

    • cites [251] Albhaisi S, Sanyal AJ, Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date. Pharmaceut Med 33, 451– 463 (2019). 31933238 source

      Not checked in the free run.

    • cites [252] Ratziu V, Charlton M, Rational combination therapy for NASH: Insights from clinical trials and error. J Hepatol, (2023). 36603662 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Organ-on-chip systems have potential to study inter-organ cross-talk such as liver-intestine, but their effectiveness has yet to be proven.

    “In theory, organ-on-chip systems have the potential to study inter-organ cross-talk, such as those between the liver and intestine; however, the effectiveness of such systems has yet to be proven.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The natural history of MASLD typically starts with fatty liver alone followed by inflammation and fibrosis, but full understanding of disease progression is lacking.

    “The natural history of MASLD typically starts with fatty liver disease alone followed by inflammation and fibrosis, but we lack a full understanding of disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Widespread adoption of organoid and organ-on-chip systems is hindered by batch-to-batch variations in primary cells and their proportions, scaling and long-term culture difficulties, lack of a complete immune component, and complex culture conditions.

    “These include batch-to-batch variations in primary cells and their proportions, difficulties associated with scaling and maintaining long-term culture, lack of a complete immune component, as well as the complex culture conditions required (245-247).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [245] Feaver RE, Cole BK, Lawson MJ, Hoang SA, Marukian S, Blackman BR, Figler RA, Sanyal AJ, Wamhoff BR, Dash A, Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight 1, (2016). PMC5135271 27942596 source

      Not checked in the free run.

    • cites [246] Kostrzewski T, Maraver P, Ouro-Gnao L, Levi A, Snow S, Miedzik A, Rombouts K, Hughes D, A Microphysiological System for Studying Nonalcoholic Steatohepatitis. Hepatology Communications 4, 77– 91 (2020). 31909357 PMC6939502 source

      Not checked in the free run.

    • cites [247] Freag MS, Namgung B, Reyna Fernandez ME, Gherardi E, Sengupta S, Jang HL, Human Nonalcoholic Steatohepatitis on a Chip. Hepatology Communications 5, 217– 233 (2021). 33553970 PMC7850303 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Organoids are grown as 3D spheroids in suspension culture and recapitulate in vivo biology more than traditional 2D cultures.

    “Organoids are grown as 3D spheroids in suspension culture and recapitulate in vivo biology more than traditional 2D cultures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Weight loss did not always correlate with fibrosis regression in recent trials with pan-PPAR and GLP1R agonists, suggesting reduced MASH is probably a more direct and better predictor of fibrosis regression than weight loss.

    “On the other hand, weight loss did not always correlate with fibrosis regression, as seen in recent clinical trials with pan-PPAR and glucagon like peptide 1 receptor (GLP1R) agonists, suggesting that reduced MASH is probably a more direct and better predictor of fibrosis regression than weight loss.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AI-based collagen morphometry indicates that fibrosis regression in MASH starts near the perisinusoidal region.

    “A recent study using artificial intelligence-based collagen morphometry assessment has indicated that fibrosis regression in MASH starts near the perisinusoidal region (258), but more rigorous validation studies are needed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Naoumov NV, Brees D, Loeffler J, Chng E, Ren Y, Lopez P, Tai D, Lamle S, Sanyal AJ, Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH. Journal of Hepatology 77, 1399– 1409 (2022). 35779659 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal models reinforce the capacity of injured liver to regress fibrosis and provide a platform for dissecting mechanisms, although mouse fibrosis regresses rapidly, possibly due to short model duration and young age.

    “Animal models reinforce the capacity of the injured liver to regress fibrosis and provide important platform for dissecting underlying mechanisms, although it should be noted that fibrosis in mice regresses incredibly rapidly, which may be in part attributed to the short duration of models (weeks to months in mice vs. years to decades in humans) and initiation of fibrosis at relatively young age (”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF, Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice. Gastroenterology 143, 1073– 1083.e1022 (2012). 22750464 PMC3848328 source

      Not checked in the free run.

    • cites [262] Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, Iwaisako K, Moore-Morris T, Scott B, Tsukamoto H, Evans SM, Dillmann W, Glass CK, Brenner DA, Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proceedings of the National Academy of Sciences 109, 9448 (2012). PMC3386114 22566629 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MASH organoids derived from iPSCs/ESCs display increased inflammatory and fibrotic responses and increased stiffness, all reversible with FGF19 treatment.

    “These MASH organoids derived from iPSCs/ESCs display increased inflammatory and fibrotic responses in addition to increased stiffness, all of which can be reversed with fibroblast growth factor 19 (FGF19) treatment (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H, Thompson W, Karns RA, Mayhew CN, McGrath PS, McCauley HA, Zhang R-R, Lewis K, Hakozaki S, Ferguson A, Saiki N, Yoneyama Y, Takeuchi I, Mabuchi Y, Akazawa C, Yoshikawa HY, Wells JM, Takebe T, Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids. Cell Metabolism 30, 374– 384.e376 (2019). 31155493 PMC6687537 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MASH fibrosis regresses spontaneously in experimental models when injury is attenuated, but few studies have focused on mechanisms of fibrosis regression in MASH.

    “Although MASH fibrosis regresses spontaneously in experimental models when injury is attenuated (275), few studies have focused on mechanisms of fibrosis regression in MASH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [275] Farooq M, Hameed H, Dimanche-Boitrel M-T, Piquet-Pellorce C, Samson M, Le Seyec J, Switching to Regular Diet Partially Resolves Liver Fibrosis Induced by High-Fat, High-Cholesterol Diet in Mice. Nutrients 14, 10.3390/nu14020386 (2022). PMC8778944 35057565 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rat TAA model of fibrosis might represent an alternative to mice because TAA-induced fibrosis no longer regresses after 6-8 weeks.

    “In contrast, the rat thioacetamide (TAA) model of fibrosis might represent a possible alternative to mice as TAA-induced fibrosis no longer regresses after 6-8 weeks on the model (263, 264).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [263] Farrell G, Schattenberg JM, Leclercq I, Yeh MM, Goldin R, Teoh N, Schuppan D, Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis. Hepatology 69, 2241– 2257 (2019). 30372785 source

      Not checked in the free run.

    • cites [264] Muller A, Machnik F, Zimmermann T, Schubert H, Thioacetamide-induced cirrhosis-like liver lesions in rats--usefulness and reliability of this animal model. Exp Pathol 34, 229– 236 (1988). 2853079 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Semi-quantitative scoring systems do not quantify the absolute amount of scar or its structural features.

    “However, these semi-quantitative scoring systems do not quantify the absolute amount of scar or its structural features.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Regulatory agencies do not yet accept digital methods in lieu of conventional fibrosis staging, but their validation and implementation is inevitable because they more accurately predict clinical outcomes than conventional staging.

    “Although regulatory agencies do not yet accept these digital methods in lieu of conventional fibrosis staging, their validation and ultimate implementation is inevitable, as they more accurately predict clinical outcomes than conventional fibrosis staging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Termination of liver injury is the most efficient way to spur fibrosis regression, where activated HSCs are removed via apoptosis or deactivation, reducing the fibrogenic cell population.

    “As noted above, termination of liver injury is the most efficient way to spur fibrosis regression, where activated HSCs are removed via apoptosis or deactivation, reducing the fibrogenic cell population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Liver stiffness by bedside elastography is increasingly popular for clinical care and approximating fibrosis severity, but is not yet suitable as a stand-alone diagnostic for clinical trials.

    “Stiffness of the liver using a bedside elastography is increasingly popular for clinical care and in approximating fibrosis severity (298), but is not yet suitable as a stand-alone diagnostic for clinical trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [298] Loomba R, Huang DQ, Sanyal AJ, Anstee QM, Trauner M, Lawitz EJ, Ding D, Ma L, Jia C, Billin A, Huss RS, Chung C, Goodman Z, Wong VW, Okanoue T, Romero-Gomez M, Abdelmalek MF, Muir A, Afdhal N, Bosch J, Harrison S, Younossi ZM, Myers RP, Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis. Gut 72, 581– 589 (2023). 36750244 PMC9905707 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    We lack a clear hierarchy of causality establishing which therapeutic targets are the most vulnerable points of attack.

    “Still, we lack a clear hierarchy of causality that establishes which are the most vulnerable points of therapeutic attack.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LOX inhibition destabilizes collagen fibers and accelerates fibrosis regression in chemically-induced fibrosis.

    “LOX inhibition destabilizes collagen fibers and accelerates fibrosis regression in chemically-induced fibrosis (273), however clinical trials of a neutralizing antibody to lysyl oxidase like 2 (LOXL2) had no effect (280).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [273] Liu SB, Ikenaga N, Peng Z-W, Sverdlov DY, Greenstein A, Smith V, Schuppan D, Popov Y, Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. The FASEB Journal 30, 1599– 1609 (2016). 26700732 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An earlier study implicated Ly6Clo macrophages in CCl4-treated mice as a potential source of proteolytic enzymes, but the human equivalent and specific proteases they secrete have not been established.

    “An earlier study implicated a specific subset of macrophages in mice treated with CCl4 that are low-Ly6C-expressing or “Ly6Clo” as a potential source of proteolytic enzymes (276, 277), but neither the human equivalent of these cells nor the specific proteases they secrete have been established.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [276] Ramachandran P, Iredale JP, Fallowfield JA, Resolution of liver fibrosis: basic mechanisms and clinical relevance. Semin Liver Dis 35, 119– 131 (2015). 25974898 source

      Not checked in the free run.

    • cites [277] Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT, Williams MJ, Dunbar DR, Manning JR, van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP, Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 109, E3186– 3195 (2012). 23100531 PMC3503234 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Stellate cell activation is regulated through coordinated expression of transcription factors governing fibrogenesis, proliferation, chemotaxis, and contractility, whereas a separate transcriptional program controls deactivation.

    “Stellate cell activation is regulated through coordinated expression of transcription factors governing fibrogenesis, proliferation, chemotaxis, and contractility, whereas a separate transcriptional program controls cellular deactivation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TIMPs produced by HSCs are increased in experimental fibrosis, which could block activity of their cognate enzymes and prevent apoptosis of activated HSCs.

    “Concurrently, tissue inhibitors of metalloproteases (TIMPs) produced by HSCs are increased in experimental fibrosis, which could block the activity of their cognate enzymes and also prevent apoptosis of activated HSCs (278, 279).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [278] Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ, Benyon C, Iredale JP, Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem 277, 11069– 11076 (2002). 11796725 source

      Not checked in the free run.

    • cites [279] Iredale JP, Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol 29, 43– 54 (1997). 9076940 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Given the heterogeneity of MASH, it may comprise multiple subtypes, each with its own vulnerabilities to therapy.

    “Indeed, given the remarkable heterogeneity of the disease, including its clinical presentation and extrahepatic co-morbidities, as well as its environmental and genetic factors, MASH may well comprise multiple subtypes, each of which has its own vulnerabilities to therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Non-invasive modalities being scrutinized include blood tests such as FIB-4, ELF, and Pro-C3/Pro-C5.

    “They range from blood tests based on standard lab parameters such as fibrosis-4 (FIB-4) (292, 293), to proprietary tests such as enhanced liver fibrosis test (ELF) (294) and type III collagen propeptide (Pro-C3)/ type V collagen propeptide (Pro-C5) (295).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [292] Udompap P, Therneau TM, Canning RE, Benson JT, Allen AM, Performance of American Gastroenterological Association Clinical Care Pathway for the risk stratification of patients with nonalcoholic fatty liver disease in the US population. Hepatology 77, 931– 941 (2023). 35989502 source

      Not checked in the free run.

    • cites [293] Canivet CM, Costentin C, Irvine KM, Delamarre A, Lannes A, Sturm N, Oberti F, Patel PJ, Decaens T, Irles-Depe M, Fouchard I, Hermabessiere P, Roux M, Barthelon J, Cales P, Powell EE, de Ledinghen V, Boursier J, Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD. Hepatology 77, 920– 930 (2023). 35822302 source

      Not checked in the free run.

    • cites [294] Wong VW, Tak WY, Goh GBB, Cheng PN, Lawitz EJ, Younossi ZM, Vuppalanchi R, Younes Z, Alkhouri N, Wang L, Liu J, Kersey K, Myers RP, Harrison SA, Goodman Z, Trauner M, Romero-Gomez M, Anstee QM, Nguyen MH, Okanoue T, Performance of Noninvasive Tests of Fibrosis Among Asians, Hispanic, and non-Hispanic Whites in the STELLAR Trials. Clin Gastroenterol Hepatol 21, 90– 102 e106 (2023). 35074532 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Diagnosis of MASH and assessment of fibrosis severity have relied on liver biopsy, but the field is moving closer to non-invasive diagnostics that will replace biopsy.

    “At the same time, although the fundamental diagnosis of MASH and assessment of fibrosis severity have relied on liver biopsy, the field is rapidly moving closer to non-invasive diagnostics that will replace biopsy, thereby accelerating clinical trial enrollment and assessment of therapeutic efficacy for candidate drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The mechanisms behind peroxidasin-induced fibrosis regression do not require its crosslinking activity towards collagen IV; rather, peroxidasin deficiency produces a hypoxic environment that reduces HSC activation and recruits pro-healing macrophages.

    “However, the mechanisms behind peroxidasin-induced fibrosis regression does not require its crosslinking activity towards collagen IV (282); rather, peroxidasin deficiency produces a hypoxic environment that reduces the activation of HSCs and recruits pro-healing macrophages (281).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [281] Sojoodi M, Erstad DJ, Barrett SC, Salloum S, Zhu S, Qian T, Colon S, Gale EM, Jordan VC, Wang Y, Li S, Ataeinia B, Jalilifiroozinezhad S, Lanuti M, Zukerberg L, Caravan P, Hoshida Y, Chung RT, Bhave G, Lauer GM, Fuchs BC, Tanabe KK, Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver. Cellular and Molecular Gastroenterology and Hepatology 13, 1483– 1509 (2022). 35093588 PMC9043497 source

      Not checked in the free run.

    • cites [282] Soudi M, Zamocky M, Jakopitsch C, Furtmüller PG, Obinger C, Molecular Evolution, Structure, and Function of Peroxidasins. Chemistry & Biodiversity 9, 1776– 1793 (2012). 22976969 PMC3533774 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum proteomics and metabolomics show considerable promise but are not yet widely implemented.

    “Serum proteomics and metabolomics techniques that measure changes in large numbers of analytes (296, 297) show considerable promise but are not yet widely implemented.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [296] Luo Y, Wadhawan S, Greenfield A, Decato BE, Oseini AM, Collen R, Shevell DE, Thompson J, Jarai G, Charles ED, Sanyal AJ, SOMAscan Proteomics Identifies Serum Biomarkers Associated With Liver Fibrosis in Patients With NASH. Hepatol Commun 5, 760– 773 (2021). 34027267 PMC8122380 source

      Not checked in the free run.

    • cites [297] Corey KE, Pitts R, Lai M, Loureiro J, Masia R, Osganian SA, Gustafson JL, Hutter MM, Gee DW, Meireles OR, Witkowski ER, Richards SM, Jacob J, Finkel N, Ngo D, Wang TJ, Gerszten RE, Ukomadu C, Jennings LL, ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. J Hepatol 76, 25– 33 (2022). 34600973 PMC8688231 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Antifibrotic drugs should primarily attack liver disease and avoid extrahepatic activity to improve tolerability and safety.

    “First, antifibrotic drugs should primarily attack the disease in liver and avoid extrahepatic activity to improve tolerability and safety.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Therapeutic targets for pre-cirrhotic and cirrhotic MASH are likely different, with pre-cirrhotic focus on attenuating inflammation and lipotoxicity, and cirrhotic focus on reducing scar content and reversing architectural distortion.

    “The therapeutic targets for these two populations are likely to be different, with a focus on attenuating inflammation and lipotoxicity as major goals prior to cirrhosis, whereas in cirrhosis, therapies need to reduce scar content and reverse architectural distortion of the liver.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Most GWAS studies seeking MASH risk variants have linked their presence to elevated AST/ALT, which helps identify gene products that modify liver injury, but not necessarily fibrosis.

    “Most GWAS studies seeking MASH risk variants have linked their presence to elevated Aspartate Transaminase (AST)/Alanine Transaminase (ALT), which helps identify gene products that modify liver injury, but not necessarily fibrosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    SNPs in PNPLA3 predict risk of more advanced disease, but this and other SNP genotypes are not yet incorporated into diagnostic algorithms.

    “Although SNPs in PNPLA3, for example, predict risk of more advanced disease, this and other SNP genotypes are not yet incorporated into diagnostic algorithms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Noninvasive tests for fibrosis could be correlated to GWAS hits, which might identify variants directly linked to fibrogenic activity rather than liver damage.

    “Noninvasive tests for fibrosis (for example using ELF, MRE, FIB-4) could in principle be correlated to GWAS hits. This approach might specifically identify variants directly linked to fibrogenic activity rather than to liver damage.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Quantification of functional hepatic reserve is conceptually attractive because function likely correlates more directly with outcomes.

    “Rather than use imaging or assessing circulating molecules from the liver, quantification of functional hepatic reserve is a conceptually attractive approach, because function is likely to correlate more directly with outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    Because FAP is also implicated in hepatic fibrosis, this LNP-mediated CAR-T approach merits further evaluation in MASH.

    “Because FAP is also implicated in hepatic fibrosis (313, 314), this approach merits further evaluation in MASH.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [313] Lee J, Byun J, Shim G, Oh YK, Fibroblast activation protein activated antifibrotic peptide delivery attenuates fibrosis in mouse models of liver fibrosis. Nature communications 13, 1516 (2022). PMC8938482 35314685 source

      Not checked in the free run.

    • cites [314] Yang AT, Kim YO, Yan XZ, Abe H, Aslam M, Park KS, Zhao XY, Jia JD, Klein T, You H, Schuppan D, Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis. Cell Mol Gastroenterol Hepatol 15, 841– 867 (2022). 36521660 PMC9972574 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Combination therapies may become necessary to improve the percentage of responders and the magnitude of response.

    “Combination therapies may become necessary to either improve the percentage of responders, as well as improving the magnitude of response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Targeting HSCs is possible by applying systemic drugs to cell receptors with restricted expression in this cell type, or by developing cell-specific lipid nanoparticles or CAR-T cells.

    “Targeting specifically to HSCs is possible either by applying systemic drugs to cell receptors with restricted expression in this cell type (for example, β-PDGFR and others uncovered using single cell technology), or by developing either cell-specific lipid nanoparticles (LNPs) or CAR-T cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Emerging technologies assess clearance of a liver-metabolized substrate or release of proteases that reflect ECM degradation in liver.

    “In liver, other emerging technologies assess either clearance of a liver-metabolized substrate (303), or release of proteases that reflect ECM degradation in liver (304).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [303] Wieland A, Etzion O, Ali RO, Levy E, Kleiner DE, Helmke SM, Heller T, Everson GT, HepQuant SHUNT Detects Portal Hypertension in Early Stages of Clinically Compensated Chronic Liver Disease. Clin Gastroenterol Hepatol, (2021). PMC8531144 33895359 source

      Not checked in the free run.

    • cites [304] Cazanave SC, Warren AD, Pacula M, Touti F, Zagorska A, Gural N, Huang EK, Sherman S, Cheema M, Ibarra S, Bates J, Billin AN, Liles JT, Budas GR, Breckenridge DG, Tiniakos D, Ratziu V, Daly AK, Govaere O, Anstee QM, Gelrud L, Luther J, Chung RT, Corey KE, Winckler W, Bhatia S, Kwong GA, Peptide-based urinary monitoring of fibrotic nonalcoholic steatohepatitis by mass-barcoded activity-based sensors. Sci Transl Med 13, eabe8939 (2021). 34669440 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    No drugs are approved yet for MASH fibrosis, and there is continued reliance on liver biopsy for FDA and EMA approvals.

    “These are still early days in the development of therapies for MASH fibrosis, with no drugs approved yet and continued reliance on liver biopsy to merit U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    An FDA advisory panel recommended against approving the FXR agonist obeticholic acid due to safety concerns, despite a significant impact on fibrosis in a phase 3 trial.

    “Among these, an FDA advisory panel has recommended against approving the FXR agonist obeticholic acid due to safety concerns, despite a significant impact on fibrosis in phase 3 trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Therapies intended to reduce hepatic fibrosis or promote regression are primarily directed to HSCs/myofibroblasts, as these are the primary source of extracellular matrix in MASH.

    “Therapies intended to reduce hepatic fibrosis or promote its regression are primarily directed to HSCs/myofibroblasts, as these are the primary source of extracellular matrix in MASH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Resmetirom showed significant benefit in both key endpoints in a phase 3 MASH trial: improvement in fibrosis without worsening MASH, and reduction in MASH without worsening fibrosis.

    “Resmetirom showed a significant benefit in both key endpoints in a phase 3 MASH trial – an improvement in fibrosis without worsening MASH, and a reduction in MASH without worsening fibrosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Large patient datasets containing both genetic analyses and non-invasive fibrosis markers would be ideal, but no such data have been reported yet.

    “Large patient datasets containing both genetic analyses and data from non-invasive fibrosis markers would be ideal for this purpose, but no such data have been reported yet.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The primary goal of treatments for MASH is to attenuate or reverse fibrosis progression before cirrhosis and to regress fibrosis if cirrhosis has developed.

    “Therefore, the primary goal of treatments for MASH is to attenuate or reverse fibrosis progression before the liver is cirrhotic, and to regress fibrosis if cirrhosis has developed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Each use-case imposes different challenges and requirements for validation requested by regulatory agencies.

    “Each of these use-cases imposes different challenges and requirements for validation requested by regulatory agencies (307).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [307] Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N, Challenges and opportunities in NASH drug development. Nat Med, (2023). 36894650 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In fibrotic disorders of other organs, functional tests are far more valuable than imaging, for example in lung or kidney.

    “Indeed, in fibrotic disorders of other organs functional tests are far more valuable than imaging, for example in lung or kidney.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Liver Forum is an all-stakeholders working group seeking to improve diagnostics in MASH.

    “Working cooperatively with these consortia has been the Liver Forum, an all-stakeholders working group seeking to improve diagnostics in MASH (310).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [310] Noureddin M, Jones C, Alkhouri N, Gomez EV, Dieterich DT, Rinella ME, Nashnet, Screening for Nonalcoholic Fatty Liver Disease in Persons with Type 2 Diabetes in the United States Is Cost-effective: A Comprehensive Cost-Utility Analysis. Gastroenterology 159, 1985– 1987 e1984 (2020). 32763241 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Dampening inflammatory signals, especially from macrophage subsets that directly stimulate myofibroblasts, is an appealing strategy.

    “Dampening the inflammatory signals, especially from macrophage subsets that directly stimulate myofibroblasts, is also an appealing strategy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Resmetirom is awaiting review by an FDA advisory panel.

    “However, the thyroid hormone beta agonist, resmetirom, is awaiting review by an FDA advisory panel.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    If resmetirom is approved, clinicians will need a way to know whether a patient is responding to justify continuation.

    “If the drug is approved, this still raises a key issue of how clinicians will know whether the patient is responding to the drug to justify its continuation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Efforts to harmonize data and accelerate progress have been supported by large consortia in North America (NIMBLE) and Europe (LITMUS).

    “Efforts to harmonize data and accelerate progress have been supported by large consortia in North America (NIMBLE)(308) and Europe (LITMUS)(309).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [308] Sanyal AJ, Shankar SS, Calle RA, Samir AE, Sirlin CB, Sherlock SP, Loomba R, Fowler KJ, Dehn CA, Heymann H, Kamphaus TN, Non-Invasive Biomarkers of Nonalcoholic Steatohepatitis: the FNIH NIMBLE project. Nat Med 28, 430– 432 (2022). 35145308 PMC9588405 source

      Not checked in the free run.

    • cites [309] Rasmussen DGK, Anstee QM, Torstenson R, Golding B, Patterson SD, Brass C, Thakker P, Harrison S, Billin AN, Schuppan D, Dufour JF, Andersson A, Wigley I, Shumbayawonda E, Dennis A, Schoelch C, Ratziu V, Yunis C, Bossuyt P, Karsdal MA, NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned. J Hepatol 78, 852– 865 (2023). 36526000 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Current liver-directed therapies include inhibitors of lipogenesis targeting FAS, DGAT, ACC, broad metabolic modulators including THRβ agonists, GLP-1R agonists, PPARs, GIPR, Aramchol, and FGF21.

    “Current liver-directed therapies include inhibitors of lipogenesis whose targets include fatty acid synthase, diacyl glycerol transferase (DGAT), ACC, broad metabolic modulators including thyroid hormone beta (THRβ) agonists, agonists of GLP-1R, PPARs and gastric inhibitory polypeptide receptor (GIPR), as well as a fatty acid-bile acid conjugate (Aramchol) and FGF21, among others (307).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [307] Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N, Challenges and opportunities in NASH drug development. Nat Med, (2023). 36894650 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Actionable SNPs such as the protective truncation variant in HSD17B13 may be valuable by designing siRNA therapies that replicate this SNP's protective action.

    “On the other hand, actionable SNPs such as the protective truncation variant in HSD17B13 (306), may be valuable by designing siRNA therapies that replicate this SNP’s protective action in patients with a disease-promoting variant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [306] Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE, A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liv source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Diagnostics for fibrosis have different contexts of use: large-scale screening, identifying advanced disease for trials, and assessing response to therapy without biopsy.

    “Diagnostics for fibrosis have different contexts of use. They can be applied large scale screening of either general populations or at-risk patients, for example those with type 2 diabetes. Alternatively, they can be used to identify patients with more advanced disease suitable for enrollment in a clinical trial, and finally, they will be necessary to assess response to therapy without requiring”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because TGFβ's pleiotropic effects include growth inhibition that attenuates cancer, systemic neutralization of this cytokine is not safe.

    “Because its pleiotropic effects include growth inhibition that attenuates cancer, however, systemic neutralization of this cytokine is not safe.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Antagonism of galectin 3 may be efficacious in patients with advanced fibrosis, with current trial results pending.

    “Antagonism of the cell surface receptor galectin 3 may be efficacious in patients with advanced fibrosis, with current trial results pending (NCT02462967, NCT04607655).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites NCT02462967

      Not checked in the free run.

    • cites NCT04607655

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An HSC-targeting liposome is in a phase 2 trial for hepatic fibrosis that delivers an siRNA to HSP47, which disrupts normal collagen folding and leads to HSC apoptosis.

    “Indeed, there is already an HSC-targeting liposome currently in a phase 2 trial for patients with hepatic fibrosis that delivers an siRNA to heat shock protein 47 (HSP47), which disrupts normal collagen folding and leads to HSC apoptosis (318).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [318] Lawitz EJ, Shevell DE, Tirucherai GS, Du S, Chen W, Kavita U, Coste A, Poordad F, Karsdal M, Nielsen M, Goodman Z, Charles ED, BMS-986263 in Patients with Advanced Hepatic Fibrosis: 36-Week Results from a Randomized, Placebo-Controlled Phase 2 Trial. Hepatology, (2021). PMC9299674 34605045

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is a Yin-Yang relationship between fibrosis and regeneration, such that drugs solely improving fibrosis could unmask regenerative activity to improve liver function and restore normal architecture, whereas drugs solely restoring hepatocyte health might unmask an endogenous antifibrotic response.

    “Conversely, there is a Yin-Yang relationship between fibrosis and regeneration, such that drugs that solely improve fibrosis could still unmask regenerative activity to improve liver function and restore normal architecture, whereas drugs that solely restore hepatocyte health might still unmask an endogenous antifibrotic response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    An alternative, less potent strategy to attenuate TGFβ activation is to block angiotensin receptors.

    “An alternative strategy to attenuate TGFβ activation, albeit less potent, is to block angiotensin receptors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pirfenidone is being explored in hepatic fibrosis.

    “Pirfenidone, an approved antifibrotic drug in pulmonary fibrosis, is being explored in hepatic fibrosis (NCT04099407).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT04099407

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A proof-of-principle study combining ACC inhibitor/FXR agonist and GLP-1R agonist improved steatosis but awaits validation with a larger follow-up biopsy trial to measure fibrosis changes.

    “One such proof of principle study combining ACC inhibitor/FXR agonist and GLP-1R agonist improved steatosis but awaits validation with a larger follow-up trial using biopsy to measure changes in fibrosis (315).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [315] Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K, Kjaer MS, Balendran C, Myers RP, Loomba R, Noureddin M, Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol 77, 607– 618 (2022). 35439567 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Molecules to block HSC-specific integrins that activate latent TGFβ are being developed and show promise in preclinical studies and early clinical trials.

    “Molecules to block HSC-specific integrins that activate latent TGFβ are being developed for this purpose, and show promise both in preclinical studies and early clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The prospect that fibrosis and regeneration are linked is supported by evidence of fibrosis regression in patients cured of viral hepatitis by antivirals, yet these agents have no direct antifibrotic activity.

    “Although still theoretical, this prospect is supported by evidence of fibrosis regression seen in patients cured of viral hepatitis by antivirals, yet these agents have no direct antifibrotic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The number of therapeutic assets in clinical trials targeting HSC activation, deactivation, or apoptosis is limited, but prospects will broaden as delivery methods improve.

    “At present, the number of therapeutic assets in clinical trials targeting these events is limited (Figure 1), but as delivery methods improve, the prospects will broaden.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The LNP-mediated approach has capacity to scale administration across many patients and sites by generating them centrally and distributing widely, similar to LNP-based COVID vaccines.

    “An exciting element of this LNP-mediated approach is its capacity to scale administration across many patients and sites by generating them in a central location, which could then distribute widely, similar to the LNP-based coronavirus disease (COVID) vaccines that were administered to billions of individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Acid ceramidase has been implicated as an activating stimulus through YAP/TAZ activation, and its inhibition is being pursued therapeutically.

    “Elegant studies have implicated acid ceramidase as an activating stimulus through YAP/TAZ activation, and therefore inhibition of acid ceramidase is being pursued therapeutically (321).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, Hu JK, Schaub JR, Ho SS, Rao V, Marlow MM, Turner SM, Sedki M, Pantano L, Ghoshal S, Ferreira DDS, Ma HY, Duwaerts CC, Espanol-Suner R, Wei L, Newcomb B, Mileva I, Canals D, Hannun YA, Chung RT, Mattis AN, Fuchs BC, Tager AM, Yimlamai D, Weaver VM, Mullen AC, Sheppard D, Chen JY, Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci Transl Med 12, (2020). PMC7976849 32817366

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGFβ1 was the first and remains the most potent fibrogenic stimulus towards HSCs and other tissue myofibroblasts, but TGFβ2 and TGFβ3 merit consideration as safer therapeutic targets.

    “TGFβ1 was the first, and remains the most potent fibrogenic stimulus towards HSCs and other tissue myofibroblasts, but as noted above, TGFβ2 and TGFβ3 merit consideration as safer therapeutic targets (147).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Sun T, Huang Z, Liang WC, Yin J, Lin WY, Wu J, Vernes JM, Lutman J, Caplazi P, Jeet S, Wong T, Wong M, DePianto DJ, Morshead KB, Sun KH, Modrusan Z, Vander Heiden JA, Abbas AR, Zhang H, Xu M, N'Diaye EN, Roose-Girma M, Wolters PJ, Yadav R, Sukumaran S, Ghilardi N, Corpuz R, Emson C, Meng YG, Ramalingam TR, Lupardus P, Brightbill HD, Seshasayee D, Wu Y, Arron JR, TGFbeta2 and TGFbeta3 isoforms drive fibrotic disease pathogenesis. Sci Transl Med 13, (2021). 34349032 source

      Not checked in the free run.

151 of 151

  • The paper relies on this without support.

    No existing studies distinguish fibrosis mechanisms or progression between lean and obese MASH.

    “There are currently no studies that distinguish fibrosis mechanisms or progression between lean and obese MASH.”

  • The paper relies on this without support.

    Current diagnostic tests lack the sensitivity to detect progressive functional changes in MASH before marked architectural disruption occurs.

    “There likely are progressive functional changes throughout the course of MASH progression, but current diagnostic tests are not sufficiently sensitive to detect them until they are accompanied by marked architectural disruption.”

  • The paper relies on this without support.

    Findings from mouse models and other chronic liver injury models can be extrapolated to human MASH fibrosis.

    “The majority of myofibroblasts in chemically-injured mouse models also derive from HSCs, and their depletion reduces liver fibrosis (52-54).”

  • The paper relies on this without support.

    ACC is the rate-limiting enzyme in de novo lipogenesis.

    “Acetyl coenzyme A carboxylase (ACC) is the rate-limiting enzyme in de novo lipogenesis.”

  • The paper relies on this without support.

    Patients with MASLD are at greater risk of death or illness from extrahepatic diseases, especially heart disease, than from liver disease until hepatic fibrosis is advanced (stage F3 or F4).

    “Because MASLD is part of a systemic disease with multiple co-morbidities, patients are at greater risk of death or illness from extrahepatic diseases, especially heart disease, than from liver disease until hepatic fibrosis is quite advanced (stage F3 or F4).”

  • The paper relies on this without support.

    No deactivation targets have yet entered clinical testing.

    “none of these targets have progressed to clinical testing yet”

  • The paper relies on this without support.

    The stellate cell clearance approaches have not yet reached clinical studies.

    “Although not yet advanced to clinical studies”

  • The paper relies on this without support.

    Fibrosis is the primary determinant of liver outcomes.

    “fibrosis is the main determinant of liver outcomes”

  • The paper relies on this without support.

    Research efforts targeting fibrogenic cells and scarring pathways are increasing.

    “efforts are intensifying to target fibrogenic cells and pathways driving the scarring response”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In MAFLD, dysregulation of adipokine secretion promotes inflammation, insulin resistance, and release of free fatty acids and proinflammatory cytokines that participate in lipotoxic hepatocyte death, hepatic inflammation, and fibrosis.

    “Proinflammatory signals originating from adipose tissue are described mainly in the context of MAFLD, where the dysregulation of adipokine secretion (i.e., increase in leptin and decrease in adiponectin) promotes inflammation, insulin resistance, and release of free fatty acids and proinflammatory cytokines that participate in lipotoxic hepatocyte death, hepatic inflammation, and fibrosis (14, 15)”

    From Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy (2024) · cites this paper as [15]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 10.1002/hep.30965 · DOI · Paper page

Cited by

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Related

Authors
Wang, S., & Friedman, S. L.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Wang, Shuang
  • Friedman, Scott L.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-10-04
Volume
15
Issue
716
Pages
eadi0759-eadi0759
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.adi0759
PMC
PMC10671253
OpenAlex
W4387330412
Cited by
158
References
317
Citations by year
2026: 57 · 2025: 61 · 2024: 40
FWCI
6.13
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (P30CA196521)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121154, R01DK128289, R01DK136016)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
nonalcoholic steatohepatitis, liver fibrosis, fibrogenesis, fibrosis regression, cellular heterogeneity, cell-cell interactions, single-cell analysis, epigenetics, genetic models, liver cirrhosis, liver cancer, non-invasive assessment
MeSH terms
Cell Communication, Fatty Liver, Humans, Liver Cirrhosis, Liver Neoplasms

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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