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Cited by 321Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Open access
Tacke, Frank, Puengel, Tobias, Loomba, Rohit, Friedman, Scott L.·2023·Journal of Hepatology
DOI 10.1016/j.jhep.2023.03.038PMC PMC12164378
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Abstract

Successful development of treatments for non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH), has been challenging. Because NASH and fibrosis lead to progression towards cirrhosis and clinical outcomes, approaches have either sought to attenuate metabolic dysregulation and cell injury, or directly target the inflammation and fibrosis that ensue. Targets for reducing the activation of inflammatory cascades include nuclear receptor agonists (e.g. resmetirom, lanifibranor, obeticholic acid), modulators of lipotoxicity (e.g. aramchol, acetyl-CoA carboxylase inhibitors) or modification of genetic variants (e.g. PNPLA3 gene silencing). Extrahepatic inflammatory signals from the circulation, adipose tissue or gut are targets of hormonal agonists (semaglutide, tirzepatide, FGF19/FGF21 analogues), microbiota or lifestyle interventions. Stress signals and hepatocyte death activate immune responses, engaging innate (macrophages, innate lymphocyte populations) and adaptive (auto-aggressive T cells) mechanisms. Therapies have also been developed to blunt immune cell activation, recruitment (chemokine receptor inhibitors), and responses (e.g. galectin-3 inhibitors, anti-platelet drugs). The disease-driving pathways of NASH converge to elicit fibrosis, which is reversible. The activation of hepatic stellate cells into matrix-producing myofibroblasts can be inhibited by antagonising soluble factors (e.g. integrins, cytokines), cellular crosstalk (e.g. with macrophages), and agonising nuclear receptor signalling. In advanced fibrosis, cell therapy with restorative macrophages or reprogrammed (CAR) T cells may accelerate repair through hepatic stellate cell deactivation or killing, or by enhancing matrix degradation. Heterogeneity of disease - either due to genetics or divergent disease drivers - is an obstacle to defining effective drugs for all patients with NASH that will be overcome incrementally.

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Crossref · 10.1016/j.jhep.2023.03.038

Cites

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Claims the paper makes

0 of 184 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Among individuals with NASH, fibrosis progresses rapidly in some but relatively slowly in others.

    “Among individuals with NASH, fibrosis progresses rapidly in some but relatively slowly in others.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Singh, 2015, Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies, Clin Gastroenterol Hepatol source

      Not checked in the free run.

  • Premisecitation

    Fibrosis stage is predictive of liver-specific morbidity and mortality.

    “fibrosis stage is predictive of liver-specific morbidity and mortality.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Sanyal, 2021, Prospective study of outcomes in adults with nonalcoholic fatty liver disease, N Engl J Med source

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    • cites [7] Simon, 2021, Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort, Gut source

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    • cites [8] Vilar-Gomez, 2018, Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study, Gastroenterology source

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  • Premisecitation

    Dietary fat and dysfunctional adipose tissue provide excessive free fatty acids.

    “dietary fat and the metabolically overwhelmed and dysfunctional adipose tissue provide excessive free fatty acids.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

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  • Premisecitation

    Excessive energy substrates, especially carbohydrates, trigger hepatic de novo lipogenesis.

    “Excessive energy substrates, especially carbohydrates, trigger hepatic de novo lipogenesis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

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  • Premisecitation

    Resolution of NASH back to NAFL can be highly dynamic and may occur even within a short time frame.

    “Resolution of NASH back to NAFL can be highly dynamic and may occur even within a short time frame.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hagstrom, 2017, Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD, J Hepatol source

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  • May combine two claims. 65
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    Lipotoxicity is a key feature of progressive NAFLD, involving production of reactive oxygen species, mitochondrial dysfunction, and endoplasmic reticulum stress.

    “lipotoxicity – defined as the generation of injurious lipid metabolites – is a key feature of progressive NAFLD, involving production of reactive oxygen species, mitochondrial dysfunction and the development of endoplasmic reticulum stress.3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

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

    Premisecitation

    The clinical course of NAFLD varies widely between patients and is shaped by both fixed and modifiable risk factors.

    “The natural course of NAFLD is heterogeneous, with substantial inter-patient variability, which is influenced by several non-modifiable (age, sex, race/ethnicity, family history, genetics) and modifiable (lifestyle/diet/exercise, comorbidities, drugs, alcohol) risk factors.2,3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Powell, 2021, Non-alcoholic fatty liver disease, Lancet source

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    • cites [3] Loomba, 2021, Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell source

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

    Interpretationreasoning

    Because fibrosis is the most compelling predictor of outcomes, current and future therapies must improve fibrosis.

    “Because fibrosis is the most compelling predictor of outcomes, current and future therapies must improve fibrosis”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    Structurally engineered fatty acids such as icosabutate improve resistance to peroxidative processes and represent a promising approach to maintaining the beneficial metabolic effects of long-chain omega-3 fatty acids.

    “Structurally engineered fatty acids, such as icosabutate, improve resistance to peroxidative processes, and thus represent a promising approach to maintaining the beneficial metabolic effects of long-chain omega-3 fatty acids.15”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Fraser, 2022, A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH, J Hepatol source

      Not checked in the free run.

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    Premisecitation

    Long-chain omega-3 fatty acids beneficially regulate inflammatory pathways in NASH, but their therapeutic efficacy is highly limited by peroxidation and subsequent degradation.

    “Long-chain omega-3 fatty acids are known to beneficially regulate inflammatory pathways in the course of NASH, but therapeutic efficacy is highly limited by peroxidation and subsequent degradation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Fraser, 2022, A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH, J Hepatol source

      Not checked in the free run.

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    Premisecitation

    Bile acids are soluble mediators and key components of the gut-liver axis, connecting altered intestinal homeostasis to metabolic injury in NAFLD.

    “For instance, bile acids are soluble mediators and key components of the gut-liver axis, connecting altered intestinal homeostasis (e.g. dysbiosis, increased permeability) to metabolic injury in NAFLD.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tilg, 2022, Gut-liver axis: pathophysiological concepts and clinical implications, Cel Metab source

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    Premisecitation

    Ample preclinical evidence supports microbiota interventions to reduce NAFLD-related liver inflammation, but evidence for long-term anti-inflammatory or antifibrotic effects in clinical trials is lacking.

    “Ample preclinical evidence supports microbiota interventions to reduce NAFLD-related liver inflammation; however, evidence for long-term anti-inflammatory or antifibrotic effects in clinical trials is lacking.43”
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    • cites [43] Albillos, 2020, The gut-liver axis in liver disease: pathophysiological basis for therapy, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reversing gut dysbiosis in NAFLD would reduce inflammatory signals, reverse gut barrier perturbations, and promote endogenous production of beneficial mediators.

    “Conceptually, reversing gut dysbiosis in NAFLD using pre-/pro-/antibiotics or faecal microbiota transplantation would reduce these inflammatory signals, reverse perturbations in gut barrier function (thereby further reducing endotoxin in the portal vein) and promote the endogenous production of beneficial mediators (FGFs, GLP-1, secondary bile acids).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Liver macrophages are key to the pathogenesis of NAFLD, as they accumulate with disease progression in human biopsies.

    “Liver macrophages are key to the pathogenesis of NAFLD (Fig. 2), as they accumulate with disease progression in human biopsies.50–52”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Guillot, 2023, Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression, Hepatology source

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    • cites [51] Kazankov, 2019, The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, Nat Rev Gastroenterol Hepatol source

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    • cites [52] Wen, 2021, Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities, Cell Mol Immunol source

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    Premisecitation

    When Kupffer cells sense hepatocyte stress and injury signals, they activate inflammatory signals, recruit monocytes via chemokines, and engulf cellular debris.

    “When Kupffer cells sense hepatocyte stress and injury signals from other cells (or extrahepatic sources), they activate inflammatory signals, recruit monocytes (and other inflammatory cells) via chemokines and engulf cellular debris.53,54”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Marra, 2014, Roles for chemokines in liver disease, Gastroenterology source

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    • cites [54] Krenkel, 2017, Liver macrophages in tissue homeostasis and disease, Nat Rev Immunol source

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  • May combine two claims.

    Premisecitation

    Activation of TLR4 via LPS leads to release of pro-inflammatory cytokines such as TNF and IL-6, and similar effects are observed if free fatty acids bind TLR4.

    “For instance, activation of TLR4 via LPS leads to the release of pro-inflammatory cytokines (e.g., TNF, interleukin [IL]-6), but similar effects are also observed if free fatty acids bind to TLR4.63”
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    • cites [63] Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest source

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    Premisecitation

    Kupffer cells comprise subsets/differentiation states, of which the CD206hi ESAM+ subtype in mice participates in fatty acid metabolism and may thereby directly drive NASH.

    “Kupffer cells comprise subsets/differentiation states, of which the CD206hi ESAM+ subtype (in mice) participates in fatty acid metabolism and may thereby directly drive NASH.56”
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    • cites [56] Bleriot, 2021, A subset of Kupffer cells regulates metabolism through the expression of CD36, Immunity source

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

    Interpretationreasoning

    Immune subsets are likely more complex and nuanced than currently understood in their functions during NASH.

    “Still, it is likely that immune subsets are more complex and nuanced than we currently understand in their functions during NASH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Given the opposing distribution of NKT cells and MAIT cells between human and mouse livers, findings about NKT cells from rodent models need to be interpreted with caution, and MAIT cells may be the human counterpart of NKT cells.

    “Given the opposing distribution of NKT cells and MAIT cells between human and mouse livers, findings about NKT cells from rodent models need to be interpreted with caution, and, from a functional perspective, MAIT cells may be the human counterpart of NKT cells.39,98”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Heymann, 2016, Immunology in the liver--from homeostasis to disease, Nat Rev Gastroenterol Hepatol source

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    • cites [98] Toubal, 2019, Mucosal-associated invariant T cells and disease, Nat Rev Immunol source

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  • May combine two claims.

    Premisecitation

    In NASH, XCR1-expressing cDC1s are found abundantly in both patients with NASH and murine steatohepatitis, and correlate with NASH severity.

    “In NASH, XCR1 (X–C motif chemokine receptor 1)-expressing cDC1s are found abundantly in both patients with NASH and murine steatohepatitis, and correlate with NASH severity.85”
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    • cites [85] Deczkowska, 2021, XCR1(+) type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis, Nat Med source

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    Premisecitation

    While many discoveries are based on mouse models, scRNA-seq analyses from human livers have identified SAMs as a unique population located in the fibrotic niche of cirrhotic livers of different disease aetiologies.

    “While many of these discoveries have been based on mouse models, scRNA-seq analyses from human livers have also identified SAMs as a unique population located in the fibrotic niche of cirrhotic livers of different disease aetiologies.74”
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    • cites [74] Ramachandran, 2019, Resolving the fibrotic niche of human liver cirrhosis at single-cell level, Nature source

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  • May combine two claims.

    Premisecitation

    In NAFLD, cytokine-neutralising antibodies are limited by missing clinical evidence of benefit on NASH or fibrosis and by poor safety profiles.

    “However, similar to the concern about using classical immunosuppressant drugs as highlighted above, their use in NAFLD is currently constrained by the lack of clinical data indicating beneficial effects on NASH and/or fibrosis, as well as their unfavourable safety profiles.79”
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    • cites [79] Wiering, 2023, Treating inflammation to combat non-alcoholic fatty liver disease, J Endocrinol

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  • May combine two claims.

    Premisecitation

    Platelets bind to hepatic macrophages, and their activation further aggravates inflammation.

    “For instance, platelets bind to hepatic macrophages, and their activation further aggravates inflammation.80”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Malehmir, 2019, Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer, Nat Med source

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  • May combine two claims.

    Premisecitation

    Infiltrating monocyte-derived macrophages can promote both fibrogenesis and fibrosis resolution.

    “These infiltrating monocyte-derived macrophages can promote both fibrogenesis71 and fibrosis resolution.72,73”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [71] Krenkel, 2018, Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis, Hepatology source

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    • cites [72] Pellicoro, 2014, Liver fibrosis and repair: immune regulation of wound healing in a solid organ, Nat Rev Immunol source

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    • cites [73] Baeck, 2014, Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice, Hepatology source

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  • May combine two claims.

    Premisecitation

    CCR2+ monocytes are important drivers of liver inflammation in NASH, and their therapeutic inhibition reduces NASH and fibrosis in rodent models.

    “C–C motif chemokine receptor (CCR)2+ monocytes are important drivers of liver inflammation in NASH, and their therapeutic inhibition reduces NASH and fibrosis in rodent models.71,76”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Krenkel, 2018, Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis, Hepatology source

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    • cites [76] Krenkel, 2017, Macrophages in nonalcoholic fatty liver disease: a role model of pathogenic immunometabolism, Semin Liver Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A population of CXCR6+ Granzyme+ PD1+ CD8+ T cells was identified in NASH livers, which are directly activated by metabolic stimuli including acetate and extracellular ATP and collectively trigger auto-aggression against hepatocytes in an antigen-independent fashion.

    “More recently, a population of CXCR6+ Granzyme+ PD1+ CD8+ T cells was identified in NASH livers, which are directly activated by metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression against hepatocytes, in an antigen-independent fashion.87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Dudek, 2021, Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH, Nature source

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  • May combine two claims.

    Interpretationreasoning

    Because inhibiting inflammatory signalling in macrophages is therapeutically challenging in NASH, augmenting anti-inflammatory signalling via targets that promote disease resolution may be the more realistic approach.

    “Because inhibiting inflammatory signalling in macrophages is therapeutically challenging in NASH, augmenting anti-inflammatory signalling via targets that promote disease resolution may be the more realistic approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Long-term risk of infection, specific side effects such as weight gain, and the lack of antigen-specific autoimmunity in NASH all argue against the use of broad immunosuppression or B-cell/T-cell targeting in NASH.

    “Long-term risk of infection, specific side effects such as weight gain, and the lack of antigen-specific autoimmunity in NASH all argue against their use in the disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In NAFLD and NASH, the NLRP3 inflammasome has been identified as a central driver of inflammation via activation of caspase 1 and release of IL-1β, and as an inducer of pyroptotic cell death.

    “In NAFLD and NASH, the NLR family pyrin domain containing 3 (NLRP3) inflammasome has been identified as a central driver of inflammation – via activation of caspase 1 and the release of inflammatory cytokines (e.g., IL-1β) – and as an inducer of inflammatory (“pyroptotic”) cell death.64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Knorr, 2020, The NLRP3 inflammasome in alcoholic and nonalcoholic steatohepatitis, Semin Liver Dis source

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  • May combine two claims.

    Interpretationreasoning

    These innate and unconventional immune cell populations are affected by interventions on the gut-liver axis and could represent promising targets for future NASH therapies.

    “These innate and unconventional immune cell populations are affected by interventions on the gut-liver axis and could represent promising targets for future NASH therapies as well.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NKT cells are much more abundant in mouse livers than in humans, and they promote NASH, fibrosis, and carcinogenesis in experimental models.

    “NKT cells are much more abundant in mouse livers than in humans, and they promote NASH, fibrosis and carcinogenesis in experimental models.86,96,97”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [86] Wolf, 2014, Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes, Cancer Cell source

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    • cites [96] Syn, 2012, NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease, Gut source

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    • cites [97] Wehr, 2013, Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis, J Immunol source

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  • May combine two claims.

    Premisecitation

    Despite favourable tolerability and antifibrotic efficacy after 1 year of treatment in adults with NASH and liver fibrosis in a phase II trial, cenicriviroc did not demonstrate sustained antifibrotic efficacy after 1 year in a larger phase III clinical trial following interim analysis, leading to termination of its development as a monotherapy in NASH.

    “However, despite favourable tolerability as well as antifibrotic efficacy after 1 year of treatment in adults with NASH and liver fibrosis in a phase II trial,78 cenicriviroc did not demonstrate sustained antifibrotic efficacy after 1 year of treatment in a larger phase III clinical trial following interim analysis, leading to the termination of its development as a monotherapy in NASH.79”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Ratziu, 2020, Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study, Hepatology source

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    • cites [79] Wiering, 2023, Treating inflammation to combat non-alcoholic fatty liver disease, J Endocrinol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NK cells are considered anti-fibrogenic due to their capacity to eliminate HSCs, but they may also support hepatic inflammation and alter metabolism.

    “For instance, NK cells are considered anti-fibrogenic due to their capacity to eliminate HSCs,91 but they may also support hepatic inflammation and alter metabolism.92”
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    • cites [91] Gur, 2012, NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis, Gut source

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    • cites [92] Martinez-Chantar, 2021, Revisiting the role of natural killer cells in non-alcoholic fatty liver disease, Front Immunol source

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

    Premisecitation

    ILC1, ILC2, and ILC3 populations have been implicated in metabolic disorders beyond NAFLD, such as obesity.

    “Of note, ILC1, ILC2 and ILC3 populations have been implicated in metabolic disorders beyond NAFLD (e.g. obesity).93,94”
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    • cites [93] O'Sullivan, 2016, Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance, Immunity source

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    • cites [94] Brestoff, 2015, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity, Nature source

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  • May combine two claims.

    Premisecitation

    Based on proteo-genomic data combined with spatial information, LAMs (SAMs) locate near intrahepatic bile ducts in homeostasis, but shift towards steatotic areas, fostered by increased CCL2 expression by HSCs.

    “Based on proteo-genomic data combined with spatial information, LAMs (SAMs) locate near intrahepatic bile ducts in homeostasis, but shift towards steatotic areas, fostered by increased C–C motif chemokine ligand 2 (CCL2) expression by HSCs.75”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Guilliams, 2022, Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches, Cell source

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  • May combine two claims.

    Premisecitation

    Neutrophils are abundant in NASH livers, particularly in early stages, and may contribute to inflammation by releasing toxic molecules including proteases, oxidants, cytokines, and NETs.

    “Neutrophils are also abundant in NASH livers, particularly in early stages, and may contribute to inflammation by releasing toxic molecules including proteases, oxidants, cytokines and NETs (neutrophil extracellular traps).81”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Jorch, 2017, An emerging role for neutrophil extracellular traps in noninfectious disease, Nat Med source

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  • May combine two claims.

    Premisecitation

    Quiescent and activated HSCs differ transcriptomically in human livers; activated HSCs downregulate vitamin A storage genes and upregulate profibrogenic genes such as collagen I.

    “In addition, quiescent and activated HSCs are transcriptomically distinct in human livers, with activated HSCs downregulating vitamin A storage-related genes and upregulating profibrogenic genes such as collagen I.113”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] MacParland, 2018, Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations, Nat Commun source

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  • May combine two claims.

    Premisecitation

    HSC activation into myofibroblasts needs energy and requires intense metabolic reprogramming through glycolysis, glutaminolysis and lipogenesis.

    “HSC activation into myofibroblasts requires energy, so that HSC activation necessitates an intense metabolic reprogramming through activation of glycolysis, glutaminolysis (using glutamine as an additional source of ATP), and lipogenesis.70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As fibrosis advances, the set of therapeutic targets changes, so early-disease treatments may work less well in advanced fibrosis.

    “Moreover, the evolution of a dense autocrine network indicates that as fibrosis advances, the repertoire of therapeutic targets evolves, so that treatments for early disease may be less effective in advanced fibrosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lipids released during autophagy provide an additional energy source for HSC activation, creating a possible antifibrotic target.

    “Intracellular lipids released during autophagy act as an additional energy source for HSC activation, revealing another therapeutic vulnerability that could be targeted by antifibrotic strategies.122”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Hernandez-Gea, 2012, Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liver wound healing is dynamic and reversible, with fibrosis regression seen after effective viral hepatitis treatment and after bariatric surgery in NASH.

    “Wound healing in the liver is dynamic and reversible,105 with ample evidence of fibrosis regression after effective treatment of viral hepatitis, and even following bariatric surgery in patients with NASH.106”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

    • cites [106] Lassailly, 2020, Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis, Gastroenterology source

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  • May combine two claims.

    Premisecitation

    The fatty acid synthase inhibitor denifanstat showed antifibrotic activity in HSCs while improving NASH.

    “Most recently, the fatty acid synthase inhibitor denifanstat (TVB-2640) also demonstrated antifibrotic activity in HSCs while improving NASH.121”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] O'Farrell, 2022, FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models, Sci Rep

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a phase IIb trial of 162 patients with NASH, cirrhosis and portal hypertension, belapectin was safe and tolerable but did not improve clinically relevant endpoints including fibrosis regression.

    “While belapectin’s safety and tolerability were good, belapectin did not improve clinically relevant endpoints including fibrosis regression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Chalasani, 2020, Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy may supply energy during HSC activation, so inhibiting autophagy would be expected to be antifibrotic.

    “As noted above, autophagy (i.e. the lysosome-dependent orderly degradation and recycling of cellular components) may generate energy during HSC activation,127 such that inhibiting autophagy would be antifibrotic.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Thoen, 2011, A role for autophagy during hepatic stellate cell activation, J Hepatol source

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  • May combine two claims.

    Premisecitation

    The acetyl-CoA carboxylase inhibitors firsocostat and clesacostat reduced liver fibrosis in animal models independently of anti-steatotic effects and reduced HSC activation in vitro.

    “The acetyl-CoA carboxylase inhibitors firsocostat, as well as clesacostat (PF-05221304), both reduced liver fibrosis in animal models, independently of their anti-steatotic effects, and HSC activation in vitro.117,118”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Bates, 2020, Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation, J Hepatol source

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    • cites [118] Ross, 2020, Acetyl-CoA carboxylase inhibition improves multiple dimensions of NASH pathogenesis in model systems, Cell Mol Gastroenterol Hepatol source

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  • May combine two claims.

    Premisecitation

    Direct TGF-β antibody therapy with fresolimumab or metelimumab has largely been stopped because of dose-limiting adverse events, since systemic inhibition is immunosuppressive and may promote cancer.

    “Targeting TGF-β directly with antibodies (e.g., fresolimumab or metelimumab) has been largely terminated due to dose-limiting adverse events, since systemic inhibition of the cytokine is immunosuppressive and may promote cancer.114”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Henderson, 2020, Fibrosis: from mechanisms to medicines, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSCs express several nuclear receptors targeted by investigational NASH drugs, including low FXR, high LXR, robust THR-α but low THR-β, and different PPAR isoforms.

    “HSCs express several nuclear receptors that a retargets of investigational drugs for NASH, including low levels of FXR, high levels of LXR, robust levels of THR-α (but low levels of THR-β) and different isoforms of PPARs.129”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Konigshofer, 2021, Nuclear receptors in liver fibrosis, Biochim Biophys Acta Mol Basis Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During HSC transdifferentiation to myofibroblasts in vitro, glucose transporters and glycolytic enzymes are induced and gluconeogenesis is downregulated.

    “During HSC transdifferentiation to myofibroblasts in vitro, glucose transporters (e.g., glucose transporter 1) and glycolytic enzymes (e.g., hexokinase 2) are induced, and gluconeogenesis is downregulated.70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hexokinase inhibitors or SGLT2 inhibitors may reduce HSC activation and fibrogenesis.

    “Thus, hexokinase inhibitors (e.g., PF-06835919) or SGLT2 (sodium glucose linked transporter 2) inhibitors like empaglifozin, licoglifozin or dapaglifozin may attenuate HSC activation and fibrogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Selective inhibition of stearoyl-CoA desaturase 1 in HSCs reduced their activation and inhibited fibrosis in rodent models.

    “The selective inhibition of stearoyl-CoA desaturase 1 in HSCs reduced their activation and inhibited fibrosis in rodent models.120”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Lai, 2017, Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Galectin 3 is released by macrophages after liver injury in NASH and promotes fibrosis.

    “Similar to cytokines, galectin 3 is secreted by macrophages upon liver injury in NASH and has profibrotic activity.102”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Al Attar, 2021, Review of galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis, Expert Rev Clin Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSC activation in NASH is driven mainly by soluble signals such as PDGF, VEGF and TGF-β, by paracrine interactions with macrophages, immune cells, hepatocytes and endothelial cells, and is accompanied by metabolic reprogramming.

    “HSC activation in NASH is mainly driven by: i) soluble signals such as platelet-derived growth factor (PDGF), vascular endothelial growth factor, and transforming growth factor (TGF)-β; ii) by paracrine interactions with macrophages and other immune cells, as well as hepatocytes and endothelial cells; it is also accompanied by metabolic reprogramming.70,108”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Gilgenkrantz, 2021, Targeting cell-intrinsic metabolism for antifibrotic therapy, J Hepatol source

      Not checked in the free run.

    • cites [108] Tsuchida, 2017, Mechanisms of hepatic stellate cell activation, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibrosis is an aberrant wound-healing process that causes scarring, loss of functional hepatocytes and chronic inflammation.

    “The disease-driving pathways of NASH converge in fibrosis (Fig. 3), an aberrant wound-healing process resulting not only in scarring (extracellular matrix deposition), but also in the loss of functional hepatocytes and chronic inflammation.104”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Schwabe, 2020, Mechanisms of fibrosis development in nonalcoholic steatohepatitis, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In alcohol-associated hepatitis, broad use of steroids, anakinra, pentoxifyllin or infliximab gives no benefit and may worsen inflammation.

    “Nonetheless, one important lesson from alcohol-associated hepatitis is that the broad application of steroids, anakinra (recombinant IL-1 receptor antagonist), pentoxifyllin (which inhibits TNF synthesis) or infliximab (anti-TNF antibody) does not provide benefit, and may aggravate this inflammatory condition.101”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Bataller, 2022, Alcohol-associated hepatitis, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proper macrophage differentiation is probably needed, because mouse models show that transferring non-programmed immature bone marrow monocytes worsens liver fibrosis, while intravenous properly ex vivo differentiated macrophages improve hepatic fibrosis.

    “However, proper macrophage differentiation is probably required, because mouse models of fibrosis have demonstrated that the adoptive transfer of “non-programmed” immature bone marrow monocytes aggravates liver fibrosis, while the intravenous administration of properly (ex vivo) differentiated macrophages ameliorates hepatic fibrosis.149,150”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [149] Thomas, 2011, Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function, Hepatology source

      Not checked in the free run.

    • cites [150] Ma, 2017, Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The clinical efficacy of macrophage therapy is unknown, and questions remain about engraftment efficiency, cell viability, phenotype stability, and whether macrophages are the best cell type.

    “Nonetheless, the clinical efficacy of this approach is unknown, and many questions remain unanswered, including the efficiency of engraftment, cell viability, phenotype stability, and whether macrophages are the optimal cell for this purpose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because HSCs/myofibroblasts, matrix proteins and fibrolytic pathways are difficult therapeutic targets, cell-based therapies are being explored to boost anti-inflammatory and antifibrotic activity.

    “Since HSCs/myofibroblasts, matrix proteins and fibrolytic pathways are challenging therapeutic targets, cell-based therapies are being explored to augment anti-inflammatory and antifibrotic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MSC transfer produced promising antifibrotic effects in mouse models, but human clinical trials with MSCs have had mixed results.

    “While MSC transfer led to promising antifibrotic effects in mouse models, clinical trials on MSCs in humans have yielded mixed results.145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Dwyer, 2021, Cell therapy for advanced liver diseases: repair or rebuild, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a proof-of-concept trial, apheresis-derived autologous CD14+ monocytes were differentiated ex vivo into a restorative phenotype; a single injection of different doses appeared safe and was associated with a slight reduction in MELD score.

    “In this proof-of-concept trial, apheresis-derived autologous CD14+ monocytes were differentiated ex vivo into a restorative phenotype (CD14+, high 25F9, CD206, CD163 and CD169). The single injection of different doses of these macrophages appeared safe and was associated with a (slight) reduction in the model of end-stage liver disease score.151”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Moroni, 2019, Safety profile of autologous macrophage therapy for liver cirrhosis, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical data with obeticholic acid show improved liver fibrosis in non-cirrhotic NASH but not in compensated cirrhosis.

    “Consistently, clinical data with obeticholic acid reported an improvement of liver fibrosis in non-cirrhotic NASH,132 but not in patients with compensated cirrhosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Younossi, 2019, Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanisms of disease regression are not well understood, but several molecular and cellular principles have been identified from mouse models and from NASH patient samples after regression.

    “The mechanisms underlying disease regression are less well understood, but several molecular and cellular principles have been identified based on mouse models24 as well as samples from patients with NASH following disease regression, for example after bariatric surgery or lifestyle modifications.137”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Peiseler, 2022, Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits, J Hepatol source

      Not checked in the free run.

    • cites [137] Haas, 2019, Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution, Nat Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages can adopt a repair phenotype that promotes fibrosis regression and tissue regeneration, supporting programmed macrophage transplantation as a therapeutic strategy.

    “Macrophages can adopt a repair phenotype that promotes fibrosis regression and proper tissue regeneration, supporting the concept of programmed macrophage transplantation as a therapeutic strategy (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hepatic fibrosis is dynamic and reversible before cirrhosis, and even cirrhosis may be reversible if not too advanced; features of advanced disease such as sinusoidal capillarisation may be less reversible.

    “Hepatic fibrosis is dynamic and reversible prior to the development of cirrhosis, and even cirrhosis may be reversible if not too advanced; however, specific features of advanced liver disease such as capillarisation of the liver sinusoids might be less reversible.105”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The absence of approved pure anti-inflammatory or antifibrotic compounds for NASH is likely due to the complexity of inflammation and fibrosis and to redundancy in their signalling.

    “However, despite the relevance of inflammation and fibrosis to NAFLD-related outcomes, no “pure” anti-inflammatory or antifibrotic compound has been approved for the treatment of NASH. This is likely related to the complexity of the processes driving inflammation and fibrosis, but also to redundancy in inflammatory and fibrogenic signalling.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: No pure anti-inflammatory or antifibrotic compound has been approved for NASH.

  • May combine two claims.

    Premisecitation

    A retinoid-conjugated lipid nanoparticle carrying siRNA against HSP47 (BMS-986263) is in phase II testing for compensated NASH cirrhosis, after showing favourable safety and some efficacy in patients regressing from HCV-associated fibrosis.

    “Currently, a retinoid-conjugated lipid nanoparticle containing small-interfering RNA against heat-shock protein 47 (HSP47, BMS-986263) is being tested in a phase II clinical trial for patients with compensated NASH cirrhosis, since it demonstrated favourable safety and some efficacy in patients regressing from hepatitis C virus-associated fibrosis.135”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Lawitz, 2022, BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial, Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Because MSCs appear to act largely through extracellular vesicles, MSC-derived extracellular vesicles could be a cell-free, less immunogenic and less toxic alternative antifibrotic strategy.

    “Since MSCs appear to exert many of their beneficial actions via the release of extracellular vesicles, the use of MSC-derived extracellular vesicles instead of cells could be an interesting cell-free, less immunogenic, and less toxic alternative antifibrotic strategy.155”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Psaraki, 2022, Extracellular vesicles derived from mesenchymal stem/stromal cells: the regenerative impact in liver diseases, Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinical translation of uPAR-directed CAR T cells is difficult because uPAR is also expressed on immune cells including neutrophils and macrophages, and senescence has cell type-dependent roles in fibrosis that may undermine senescent-cell depletion.

    “Nonetheless, the clinical translation of this approach is challenging because uPAR is not only expressed on senescent cells, but also on several immune cell populations including neutrophils and macrophages, and cellular senescence has cell type-dependent functions in fibrosis that may undermine efforts to deplete senescent cells as a therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Efforts to target fibrogenic cells in the heart by targeting cell surface FAP-1 are encouraging and may be adaptable to liver disease.

    “On the other hand, other efforts to target fibrogenic cells in the heart by targeting cell surface FAP-1 (fibroblast activating protein) are very encouraging, and may be adaptable to liver disease.147,148”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Friedman, 2022, Fighting cardiac fibrosis with CAR T cells, N Engl J Med source

      Not checked in the free run.

    • cites [148] Rurik, 2022, CAR T cells produced in vivo to treat cardiac injury, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Targeting critical downstream inflammation and fibrosis pathways, such as by depleting immune cells or antagonising cytokines, risks undermining immune surveillance and is unacceptably risky for chronic NASH.

    “Moreover, targeting critical downstream pathways of inflammation and fibrosis, for example by depleting immune cells or antagonising cytokines, carries a high risk of undermining important immune surveillance functions,158 making such approaches unacceptably risky for a chronic condition such as NASH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Jenne, 2013, Immune surveillance by the liver, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myofibroblasts can be deactivated or eliminated by reverting them to a quiescent HSC-like phenotype, by HSC senescence, or by NK-cell or T-cell elimination of activated HSCs.

    “iii) deactivation or elimination of myofibroblasts by reverting them to a quiescent HSC-like phenotype, via HSC senescence or by elimination of activated HSCs via NK cells or T cells 91,105,141;”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [91] Gur, 2012, NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis, Gut source

      Not checked in the free run.

    • cites [105] Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

    • cites [141] Koda, 2021, CD8(+) tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells, Nat Commun source

      Not checked in the free run.

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

    Interpretationnone given

    Efficient cytotherapy will require long-term stability of a repair macrophage phenotype.

    “Regardless, efficient cytotherapy will require long-term stability of a “repair macrophage” phenotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HSC specificity is critical because some so-called HSC-specific nanoparticles target macrophages, possibly through phagocytic capacity.

    “However, HSC specificity is critical as some “HSC-specific nanoparticles” target macrophages, possibly through their phagocytic capacity.136”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Ergen, 2019, Liver fibrosis affects the targeting properties of drug delivery systems to macrophage subsets in vivo, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Combining anti-inflammatory strategies could amplify the efficacy of metabolic drugs and overcome signalling redundancies, supporting combinatorial treatment for NASH.

    “This would, however, support the concept of combinatorial treatment for NASH, as combining anti-inflammatory strategies could amplify the efficacy of metabolic drugs and overcome signalling redundancies.156”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Ratziu, 2023, Rational combination therapy for NASH: insights from clinical trials and error, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Full matrix degradation also requires lower levels of MMP-inhibitory proteins such as TIMP and the presence of phagocytic macrophages.

    “Full matrix degradation also requires reduced levels of MMP-inhibitory proteins (e.g. TIMP [tissue inhibitor of MMP]) and the presence of phagocytic macrophages.142”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Caligiuri, 2021, Cellular and molecular mechanisms underlying liver fibrosis regression, Cells

      Not checked in the free run.

69 of 69

  • The paper relies on this without support.

    Inflammation and fibrosis are evolutionarily conserved endogenous defence mechanisms.

    “However, inflammation and fibrosis represent evolutionarily conserved, endogenous defence mechanisms, so that targets for intervention must be selected carefully”

  • The paper relies on this without support.

    The gut and liver form an anatomically and functionally linked unit, the gut-liver axis.

    “since the gut and liver form an anatomically and functionally linked unit, the “gut-liver axis”.”

  • The paper relies on this without support.

    Many harmful effects of NASH inflammation, including hepatocyte death and activation of fibrogenic myofibroblasts, are mediated by soluble factors.

    “Many of the detrimental effects of inflammation in NASH – including death of hepatocytes and activation of fibrogenic myofibroblast populations – are mediated by soluble factors.”

  • The paper relies on this without support.

    The body has evolved many overlapping mechanisms that preserve inflammation and fibrogenesis for tissue homeostasis or damage control.

    “In order to ensure tissue homeostasis or – in the case of injury – damage control, the body has evolved many overlapping mechanisms to preserve inflammation and fibrogenesis.”

  • The paper relies on this without support.

    Many cellular components of liver fibrosis can adapt their phenotypes to the hepatic microenvironment.

    “In fact, many cellular components of liver fibrosis show a tremendous capacity to adapt their phenotypes towards the hepatic microenvironment, making it challenging to treat the disease if the tissue injury is ongoing.”

  • The paper relies on this without support.

    No pure anti-inflammatory or antifibrotic compound has been approved for NASH.

    “However, despite the relevance of inflammation and fibrosis to NAFLD-related outcomes, no “pure” anti-inflammatory or antifibrotic compound has been approved for the treatment of NASH.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Inflammasome activation and inhibition are both presented as treatment strategies

    Minor

    One passage describes activating the inflammasome as a way to block danger recognition, but the following passage proposes inhibiting its activation to treat NASH. The stated directions of intervention conflict.

1 of 1

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Authors
Tacke, F., Puengel, T., Loomba, R., & Friedman, S. L.
Affiliations
  • Stiftung Charité (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
  • University of California San Diego (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Tacke, Frank
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2023-08
Volume
79
Issue
2
Pages
552-566
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2023.03.038
PMC
PMC12164378
OpenAlex
W4365517553
Cited by
321
References
162
Citations by year
2026: 84 · 2025: 112 · 2024: 93 · 2023: 31
FWCI
12.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (P01HL147835)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK120515, R01DK106419, R01DK121378, R01DK124318, U01DK061734, U01DK130190)
  • National Center for Advancing Translational Sciences (5UL1TR001442)
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (3UL1TR004419, 5P30CA196521, R01 DK 121154-01A1, R01 DK128289)
  • Bundesministerium für Bildung und Forschung
  • National Institute on Alcohol Abuse and Alcoholism (U01AA029019)
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, non-alcoholic fatty liver disease, liver fibrosis, anti-inflammatory therapy, antifibrotic therapy, nuclear receptor agonists, obeticholic acid, lanifibranor, resmetirom, semaglutide, tirzepatide, gut microbiota, adipose tissue inflammation, hepatocyte death, innate lymphoid cells, macrophages, galectin-3 inhibitors, chemokine receptor inhibitors, hepatic stellate cells, myofibroblasts, cell therapy, chimeric antigen receptor T cells, disease heterogeneity
MeSH terms
Anti-Inflammatory Agents, Humans, Liver, Liver Cirrhosis, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Non-alcoholic Fatty Liver Disease

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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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