Immunopathogenic mechanisms and immunoregulatory therapies in MASLD
Open accessAbstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, with an estimated global prevalence of approximately 30%; however, effective pharmacotherapies are still limited due to its complex pathogenesis and etiology. Therefore, a more thorough understanding of disease pathogenesis is urgently needed. An increasing number of studies suggest that MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are driven by chronic overnutrition, multiple genetic susceptibility factors, and pathogenic consequences, including hepatocyte damage and liver inflammation. Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis. Current therapies for MASH, including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics, mainly target metabolic injury to the liver but not inflammation directly. In this review, we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.
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Infiltrating monocytes actively replace embryonic Kupffer cells during injury.
“In addition to competing for survival signals like CSF-1 (9, 33, 34), infiltrating monocytes actively replace embryonic KCs (EmKCs) during injury (35–37).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [37]
The “Role of resident Kupffer cells and infiltrating macrophages” section says EmKCs are depleted and replaced by bone marrow-derived macrophages during MASLD development, with monocyte-derived macrophages gradually entering the KC pool. This supports replacement in MASLD, but the source does not establish that it occurs during injury generally; page numbers were not supplied. (LLM, conf=0.83)
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“In addition, NETs are able to promote the differentiation of regulatory T cells (Tregs), which contribute to carcinogenesis in MASLD [76], whereas activating PPAR α can reduce NET formation in a high-fat diet (HFD) context [111].”
Liver macrophages in health and disease
Guilliams, M., & Scott, C. L. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.002 · Cited by 395 · cited 1× · see citing works
“KCs are iron storage cells that play a key role in iron metabolism [54].”
A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice
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“Strikingly, mtDNA from lipotoxicity-induced hepatocytes induced TNF-α and IL-6 expression in Kupffer cells, whereas STING de fi ciency attenuated this in fl ammation, suggesting that STING functions as a mtDNA sensor in Kupffer cells, contributing to MASH progression [131].”
Cahill, T. J., Thomsen, A. R. B., Tarrasch, J. T., Plouffe, B., Nguyen, A. H., Yang, F., Huang, L.-Y., Kahsai, A. W., Bassoni, D. L., Gavino, B. J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701529114 · Cited by 382 · cited 1× · see citing works
“…much interest because of its importance and heterogeneity. β -Arrestin 2, a multifunctional adaptor protein for the desensitization and internalization of G protein-coupled receptors (GPCRs) [99], was found to be elevated in liver macrophages and circulating monocytes in patients with MASH.”
Daemen, S., Gainullina, A., Kalugotla, G., He, L., Chan, M. M., Beals, J. W., Liss, K. H., Klein, S., Feldstein, A. E., Finck, B. N., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108626 · Cited by 378 · cited 4× · see citing works
“Ccr2 − / − mice, which lack hepatic LAMs, exhibit exacerbated MASH [28].”
InfluentialIsraelsen, M. E., Francque, S., Tsochatzis, E. A., & Krag, A. A. (2024) · The Lancet · doi:10.1016/s0140-6736(24)01811-7 · Cited by 370 · cited 1× · see citing works
“…disease ” to “ steatotic liver disease ” , which includes all conditions characterized by abnormal hepatic lipid accumulation and encompasses MASLD, alcohol-associated liver disease (ALD), metabolic dysfunction, alcohol-associated liver disease (MetALD) and other rare causes of liver steatosis [9].”
Hildreth, A. D., Ma, F., Wong, Y. Y., Sun, R., Pellegrini, M. A., & O’Sullivan, T. E. (2021) · Nature Immunology · doi:10.1038/s41590-021-00922-4 · Cited by 358 · cited 1× · see citing works
“Investigating cell ‒ cell ligand ‒ receptor interactions and obesity-enriched signaling pathways in white adipose tissue (WAT) [154] highlighted a dramatic shift from immunoregulatory mechanisms in lean WAT to the establishment of in fl ammatory networks in obese WAT.”
Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer
Ku, H.-C., & Cheng, C.-F. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00556 · Cited by 345 · cited 1× · see citing works
“Activating transcription factor 3 (ATF3), a stress-induced transcription factor that binds to the cyclic AMP response element (CRE), plays a vital role in metabolic regulation and immunity [101].”
du Plessis, J., van Pelt, J. F., Korf, H., Mathieu, C., der Schueren, B. V., Lannoo, M., Oyen, T., Topal, B., Fetter, G., Nayler, S., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.044 · Cited by 324 · cited 1× · see citing works
“These macrophages produce elevated levels of cytokines in culture, establishing a clear link between adipose tissue in fl ammation and advanced liver disease [153].”
Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge
Pellicci, D. G., Koay, H., & Berzins, S. P. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0345-y · Cited by 322 · see citing works
An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH
Tacke, F., Puengel, T., Loomba, R., & Friedman, S. L. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.03.038 · Cited by 321 · cited 2× · see citing works
“…in MASLD is rarely linear in its development and progression; rather, it fl uctuates between fl ares and resolution, which may explain why the highly dynamic parameter of in fl ammation is a weaker prognostic feature than fi brosis when it is captured at a single time point via liver histology [172].”
Self-citationNonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
Francque, S., Szabo, G., Abdelmalek, M. F., Byrne, C. D., Cusi, K., Dufour, J.-F., Roden, M., Sacks, F., & Tacke, F. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00366-5 · Cited by 316 · see citing works
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“Lani fi branor is a pan-PPAR agonist that modulates key metabolic, in fl ammatory, and fi brogenic pathways in the pathogenesis of experimental MASH models [200].”
Self-citationWong, C. K., McLean, B. A., Baggio, L. L., Koehler, J. A., Hammoud, R., Rittig, N., Yabut, J. M., Seeley, R. J., Brown, T. J., & Drucker, D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.11.009 · Cited by 304 · cited 1× · see citing works
“For example, central GLP-1R activation inhibits Toll-like receptor agonist-induced in fl ammation, thus reducing the severity of polymicrobial in fl ammation [180].”
Mucosal-associated invariant T cells and disease
Toubal, A., Nel, I., Lotersztajn, S., & Lehuen, A. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0191-y · Cited by 300 · see citing works
Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223
Calvente, C. J., Tameda, M., Johnson, C. D., del Pilar, H., Lin, Y. C., Adronikou, N., De Mollerat Du Jeu, X., Llorente, C., Boyer, J., & Feldstein, A. E. (2019) · Journal of Clinical Investigation · doi:10.1172/jci122258 · Cited by 268 · cited 1× · see citing works
“In addition, it has been reported that miR-223 also mediates the function of neutrophils in spontaneous resolution of liver fi brosis [118].”
GDF15 promotes weight loss by enhancing energy expenditure in muscle
Wang, D., Townsend, L. K., DesOrmeaux, G. J., Frangos, S. M., Batchuluun, B., Dumont, L., Kuhre, R. E., Ahmadi, E., Hu, S., Rebalka, I. A., et al. (2023) · Nature · doi:10.1038/s41586-023-06249-4 · Cited by 266 · cited 1× · see citing works
“Although GDF15 is a promising target for obesity [160, 161], the function and cellular source of GDF15 during MASLD are not fully understood.”
Wang, X., He, Q., Zhou, C., Xu, Y., Liu, D., Fujiwara, N., Kubota, N., Click, A., Henderson, P., Vancil, J., et al. (2023) · Immunity · doi:10.1016/j.immuni.2022.11.013 · Cited by 262 · cited 2× · see citing works
“Hepatocyte-derived sphingosine-1 phosphate (S1P) was also shown to induce Trem2 expression in macrophages [39].”
Benedé-Ubieto, R., Cubero, F. J., & Nevzorova, Y. A. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2331460 · Cited by 242 · cited 1× · see citing works
“The complicated progression of MASLD extends beyond the liver, driven by the “ gut ‒ liver axis ” , where diet and genetic and gut ‒ liver interactions affect disease outcomes [164].”
Hou, J., Zhang, J., Cui, P., Zhou, Y., Liu, C., Wu, X., Ji, Y., Wang, S., Cheng, B., Ye, H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci135197 · Cited by 239 · cited 3× · see citing works
“Strikingly, Trem2 -de fi cient macrophages release exosomes that impair hepatocytic mitochondrial structure and energy supply due to their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2) expression in MASLD [38].”
InfluentialThe Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity
Van Herck, M. A., Weyler, J., Kwanten, W. J., Dirinck, E. L., De Winter, B. Y., Francque, S. M., & Vonghia, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00082 · Cited by 238 · cited 1× · see citing works
“Although a role of CD4 + T cells in MASLD has been suggested [72], the exact polarization state of these cells during MASLD development remains obscure.”
A subset of Kupffer cells regulates metabolism through the expression of CD36
Blériot, C., Barreby, E., Dunsmore, G., Ballaire, R., Chakarov, S., Ficht, X., De Simone, G., Andreata, F., Fumagalli, V., Guo, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.006 · Cited by 236 · cited 2× · see citing works
“…population (KC1) and a minor CD206 high ESAM + population (KC2), only KC2-expressing genes are involved in liver metabolism regulation, including fatty acid metabolism both in steady-state and in diet-induced obesity in mice, as well as steatosis induction via the fatty acid transporter CD36 [52].”
Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver
Hegde, P., Weiss, E., Paradis, V., Wan, J., Mabire, M., Sukriti, S., Rautou, P.-E., Albuquerque, M., Picq, O., Gupta, A. C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04450-y · Cited by 232 · cited 1× · see citing works
“Experimental evidence supports pro fi brogenic functions in chronically injured livers, and inhibiting MAIT cells promotes fi brosis regression via the induction of a repair phenotype in hepatic macrophages [93 – 95].”
Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases
Herre, M., Cedervall, J., Mackman, N., & Olsson, A. (2022) · Physiological Reviews · doi:10.1152/physrev.00062.2021 · Cited by 232 · see citing works
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“Notch signaling is a highly conserved pathway that serves as the primary juxtacrine signaling pathway used for direct cell-to-cell communication between adjacent cells, in fl uencing numerous cell fate decisions in the development of multicellular organisms [125].”
Krenkel, O., Hundertmark, J., Abdallah, A. T., Kohlhepp, M., Puengel, T., Roth, T., Branco, D. P. P., Mossanen, J. C., Luedde, T., Trautwein, C., et al. (2020) · Gut · doi:10.1136/gutjnl-2019-318382 · Cited by 220 · cited 1× · see citing works
“The majority of hepatic MASH macrophages are derived from recruited bone marrow-derived macrophages, which have diverse functions, as they adapt their phenotype ( “ polarization ” ) in response to the local environment [57].”
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“Given the strong induction of Trem2 expression during MASH, circulating levels of soluble Trem2 (sTrem2) in MASH were demonstrated to correlate with disease severity in mice and humans [37].”
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“…analysis revealed that CD69 + CD103 - CD8 + tissue-resident memory (Trm) cells were enriched in the livers subjected to MASH resolution, which attracted hepatic stellate cells in a CCR5-dependent manner and resulted in HSC apoptosis, thereby promoting MASH-related liver fi brosis resolution [82].”
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
Newsome, P. N., & Ambery, P. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.033 · Cited by 211 · cited 1× · see citing works
“In addition, dual and triple incretin agonists that combine GLP-1 with glucagon or GIP (glucose-dependent insulinotropic polypeptide) activity to enhance metabolic effects are being developed [187].”
Barrow, F., Khan, S., Fredrickson, G., Wang, H., Dietsche, K., Parthiban, P., Robert, S., Kaiser, T., Winer, S., Herman, A., et al. (2021) · Hepatology · doi:10.1002/hep.31755 · Cited by 210 · cited 1× · see citing works
“B-cell de fi ciency mitigated MASH progression, and adoptively transferring B cells for MASH livers recapitulated the disease [84].”
FXR agonists in NASH treatment
Adorini, L., & Trauner, M. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.034 · Cited by 197 · cited 2× · see citing works
“In the past decade, numerous FXR agonists have been assessed for the treatment of MASH, although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose limiting, as summarized in a previous review [192].”
Dasgupta, D., Nakao, Y., Mauer, A. S., Thompson, J., Sehrawat, T. S., Liao, C., Krishnan, A., Lucien, F., Guo, Q., Liu, M., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.06.031 · Cited by 188 · cited 1× · see citing works
“…extracellular vesicles (EVs) facilitate monocyte adhesion via integrin β 1 (ITG β 1)- dependent pathways [140], whereas IRE1A activation in hepatocytes induces the release of ceramide-enriched EVs, which further recruit monocyte-derived macrophages and exacerbate liver in fl ammation [141].”
Harrison, S. A., Browne, S., Suschak, J. J., Tomah, S., Gutierrez, J. A., Yang, J., Roberts, M. S., & Harris, M. S. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.07.006 · Cited by 187 · cited 1× · see citing works
“…clinical trial (NCT05006885) revealed that pemvidutide, a GLP-1/glucagon dual receptor agonist, may be an effective treatment for MASH, as pemvidutide treatment signi fi cantly reduced liver fat content, noninvasive biomarkers of liver in fl ammation, and body weight compared with placebo [188].”
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“Owing to substantial underreporting and little recognition of the effect of alcohol on SLD, a more accurate prognose and effective management of SLD, addressing both metabolic and alcohol-related factors is crucial to appropriately diagnose, manage, and address the disease [222, 223].”
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“Among these miRNAs, miR-223 is broadly recognized as a protective factor in MASLD via myeloid cell-to-hepatocyte communication by targeting several in fl amma-tory genes and oncogenes in hepatocytes to prevent MASH and MASLD-HCC [116, 117].”
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Interleukin‐22 Ameliorates Neutrophil‐Driven Nonalcoholic Steatohepatitis Through Multiple Targets
Hwang, S., He, Y., Xiang, X., Seo, W., Kim, S., Ma, J., Ren, T., Park, S. H., Zhou, Z., Feng, D., et al. (2019) · Hepatology · doi:10.1002/hep.31031 · Cited by 180 · cited 1× · see citing works
“A previous study revealed that IL-22 reversed neutrophil-derived reactive oxygen species and the activation of stress kinases via the induction of metallothionein in hepatocytes, ultimately ameliorating MASH [212].”
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“To date, the ef fi cacy of agents that directly target immune cell function and recruitment is still lacking, since the dual CCR2/CCR5 inhibitor cenicriviroc did not demonstrate anti fi brotic ef fi cacy after 1 year of treatment in MASH patients with liver fi brosis in a phase III trial [176].”
Self-citationA proteo-transcriptomic map of non-alcoholic fatty liver disease signatures
Govaere, O., Hasoon, M., Alexander, L., Cockell, S., Tiniakos, D., Ekstedt, M., Schattenberg, J. M., Boursier, J., Bugianesi, E., Ratziu, V., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00775-1 · Cited by 178 · cited 1× · see citing works
“Furthermore, in a multicenter proteomic study, a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and Trem2), body mass index and type 2 diabetes mellitus status was used to identify at-risk MASH [43].”
Neutrophils in liver diseases: pathogenesis and therapeutic targets
Liu, K., Wang, F., & Xu, R. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00560-0 · Cited by 177 · cited 1× · see citing works
“However, neutrophils can also be pathogenic by releasing various in fl ammatory mediators, including different cytokines, myeloperoxidase (MPO), reactive oxygen species (ROS), and proteases [65].”
UCP1 governs liver extracellular succinate and inflammatory pathogenesis
Mills, E., Harmon, C., Jedrychowski, M. P., Xiao, H.-P., Garrity, R., Tran, N. V., Bradshaw, G. A., Fu, A., Szpyt, J., Reddy, A., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00389-5 · Cited by 176 · cited 1× · see citing works
“The de fi ciency of UCP1 led to elevated extracellular succinate in liver tissue, thereby driving in fl ammation via succinate receptor 1 (SUCNR1) in liver-resident stellate cells and macrophage populations [158].”
Harrison, S. A., Rolph, T., Knott, M., & Dubourg, J. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.034 · Cited by 176 · cited 2× · see citing works
“Fibroblast growth factor 21 (FGF21), an endocrine FGF primarily produced in the liver, protects against MASH [50].”
NKp46-Mediated Killing of Human and Mouse Hepatic Stellate Cells Attenuates Liver Fibrosis
Gur, C., Doron, S., Kfir-Erenfeld, S., Horwitz, E., Abu-tair, L., Safadi, R., & Mandelboim, O. (2012) · Gut · doi:10.1136/gutjnl-2011-301400 · Cited by 173 · cited 1× · see citing works
“Mechanistically, NKp46/NCR1, a speci fi c marker of NK cells, mediates the killing of human and mouse HSCs through unknown ligands, thus resulting in the attenuation of liver fi brosis [88].”
The benefits of GLP-1 drugs beyond obesity
Drucker, D. J. (2024) · Science · doi:10.1126/science.adn4128 · Cited by 169 · cited 1× · see citing works
“Recently, GLP-1 receptor (GLP-1R) and its agonists have garnered widespread attention in the medical community because they are highly potent treatments for obesity and type 2 diabetes [178].”
Yoshida, S., Ikenaga, N., Liu, S. B., Peng, Z.-W., Chung, J., Sverdlov, D. Y., Miyamoto, M., Kim, Y. O., Ogawa, S., Arch, R. H., et al. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.08.038 · Cited by 164 · cited 1× · see citing works
“Accumulating studies suggest that aspirin exerts anti-in fl ammatory and antitumor effects by inhibiting cyclooxygenase-2 and platelet-derived growth factor signaling, representing a promising and low-cost strategy for the treatment of MASLD [207 – 209].”
The gut vascular barrier: a new player in the gut–liver–brain axis
Brescia, P., & Rescigno, M. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.06.007 · Cited by 158 · see citing works
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“…-de fi cient mice are resistant to diet-induced metabolic disorders, as evidenced by fewer hepatic foamy macrophages, reduced in fl ammation, improved glucose tolerance and hepatic lipid metabolism [61], suggesting that blocking MSR1 signaling could be a promising approach for the treatment of MASLD.”
Moreno‐Fernandez, M. E., Giles, D. A., Oates, J. R., Chan, C. C., Damen, M. S. M. A., Doll, J., Stankiewicz, T. E., Chen, X., Chetal, K., Karns, R. A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.04.018 · Cited by 158 · cited 3× · see citing works
“…lymphocyte recruitment is mediated by distinct chemokine axes, including the CXCR6 ‒ CXCL16 pathway for natural killer T (NKT) cells, the CXCR3 ‒ CXCL9 ‒ CXCL10 pathway for in fl ammatory hepatic CXCR3 + Th17 (ihTh17) cells, and the CCR2 ‒ CCR5 signaling pathway for γδ T cells [74, 144, 146, 147].”
Roles of Regulatory T Cells in Tissue Pathophysiology and Metabolism
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“Although Tregs support tissue function and tissue homeostasis by limiting in fl ammation and promoting repair [75], the functions of Tregs in MASLD initiation and progression are not fully understood.”
He, Y., Hwang, S., Cai, Y., Kim, S., Xu, M., Yang, D., Guillot, A., Feng, D., Seo, W., Hou, X., et al. (2019) · Hepatology · doi:10.1002/hep.30645 · Cited by 150 · cited 1× · see citing works
“Among these miRNAs, miR-223 is broadly recognized as a protective factor in MASLD via myeloid cell-to-hepatocyte communication by targeting several in fl amma-tory genes and oncogenes in hepatocytes to prevent MASH and MASLD-HCC [116, 117].”
Self-citationThe diverse roles of neutrophils from protection to pathogenesis
Herro, R., & Grimes, H. L. (2024) · Nature Immunology · doi:10.1038/s41590-024-02006-5 · Cited by 149 · cited 1× · see citing works
“Neutrophils are the most abundant leukocytes in the blood and form a critical arm of innate immunity, playing a well-recognized role in antibacterial defense by extruding a meshwork of chromatin fi bers to establish neutrophil extracellular traps (NETs) via a process known as NETosis [63, 64].”
Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2
Ganguly, S., Rosenthal, S. B., Ishizuka, K., Troutman, T. D., Rohm, T. V., Khader, N., Aleman-Muench, G., Sano, Y., Archilei, S., Soroosh, P., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2405746121 · Cited by 145 · cited 7× · see citing works
“A recent study indicated that macrophage heterogeneity in livers undergoing MASH regression closely mirrors that of active MASH [25].”
InfluentialSelf-citationThe bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease
Sawada, K., Chung, H., Softic, S., Moreno-Fernandez, M. E., & Divanovic, S. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.009 · Cited by 139 · see citing works
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“For example, high-fat diet-induced ATM activation triggers the upregulation of proin fl am-matory gene expression in mouse models [151].”
Sanyal, A. J., Ratziu, V., Loomba, R., Anstee, Q. M., Kowdley, K. V., Rinella, M. E., Sheikh, M. Y., Trotter, J. F., Knapple, W., Lawitz, E. J., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.014 · Cited by 137 · see citing works
Immunopathobiology and therapeutic targets related to cytokines in liver diseases
He, Y., Hwang, S., Ahmed, Y. A., Feng, D., Li, N., Ribeiro, M. D. C., Lafdil, F., Kisseleva, T., Szabó, G., & Gao, B. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00580-w · Cited by 136 · cited 1× · see citing works
“IL-22 functions as a tissue-protective cytokine during liver injury by activating STAT3 in hepatocytes through a receptor complex composed of IL-22R1 and IL-10R2 [211].”
Self-citationNew and emerging treatments for metabolic dysfunction-associated steatohepatitis
Tincopa, M. A., Anstee, Q. M., & Loomba, R. S. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.011 · Cited by 133 · see citing works
Gao, H., Jin, Z., Bandyopadhyay, G. K., Rocha, K. C. E., Liu, X., Zhao, H., Zhang, D., Jouihan, H. A., Pourshahian, S., Kisseleva, T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.05.008 · Cited by 127 · cited 1× · see citing works
“Treating MASH mice with miR-690 inhibited hepatic steatosis, fi brosis and in fl ammation [119].”
Self-citationThe role of macrophage scavenger receptor 1 (MSR1) in inflammatory disorders and cancer
Gudgeon, J., Marín‐Rubio, J. L., & Trost, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1012002 · Cited by 126 · see citing works
Loomba, R. S., Bédossa, P., Grimmer, K., Kemble, G. W., Martins, E. B., McCulloch, W. F., O’Farrell, M., Tsai, W.-W., Cobiella, J., Lawitz, E., et al. (2024) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(24)00246-2 · Cited by 121 · cited 1× · see citing works
“Another example of a “ metabolic drug ” is denifanstat, an oral fatty acid synthase (FASN) inhibitor, which led to statistically signi fi cant improvements in disease activity, MASH resolution, and fi brosis in a multicenter, double-blind, randomized, placebo-controlled phase 2b trial [175].”
m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity
Qin, Y., Li, B., Arumugam, S., Lu, Q., Mankash, S. M., Li, J., Sun, B., Li, J., Flavell, R. A., Li, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109968 · Cited by 118 · cited 1× · see citing works
“…regulating cell growth and survival, particularly under various stress conditions, and its transcripts are m 6 A-decorated to decrease its mRNA stability, leading to reduced protein levels of DDIT4, whereas the induction of DDIT4 can mitigate MASLD by reducing macrophage effector function [124].”
Guillot, A., Winkler, M., Silva Afonso, M., Aggarwal, A., Lopez, D., Berger, H., Kohlhepp, M. S., Liu, H., Özdirik, B., Eschrich, J., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000270 · Cited by 116 · cited 1× · see citing works
“In human liver biopsies, the accumulation of macrophages is closely associated with the severity of MASH and fi brosis [26].”
Self-citationSavage, T. M., Fortson, K. T., de los Santos-Alexis, K., Oliveras-Alsina, A., Rouanne, M., Rae, S. S., Gamarra, J. R., Shayya, H., Kornberg, A., Cavero, R., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.009 · Cited by 115 · cited 1× · see citing works
“Mechan-istically, Areg can activate pro fi brotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling and promote hepatocyte gluconeogenesis via IL-6 [79].”
Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC
Xia, Y., Wang, Y., Xiong, Q., He, J., Wang, H., Islam, M., Zhou, X., Kim, A. C., Zhang, H., Huang, H., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000000762 · Cited by 113 · cited 2× · see citing works
“Neutrophil in fi ltration and NET formation are increased during the development of MASLD [68, 69], and NETs reportedly promote MASH by inducing metabolic reprogramming of HSCs [68].”
The chromosome folding problem and how cells solve it
Dekker, J., & Mirny, L. A. (2024) · Cell · doi:10.1016/j.cell.2024.10.026 · Cited by 112 · cited 1× · see citing works
“…including chromatin structure and chromatin stability, are involved in the role of immune cells in MASLD is largely unknown, but newer technologies, such as 5 C, Hi-C, Micro-C, DNAse-Hi-C, Chia-PET, HiChIP, and Plac-seq, are expected to decipher the understanding of chromosome conformation [122].”
Babuta, M., Morel, C., Ribeiro, M. D. C., Calenda, C. D., Ortega‐Ribera, M., Nagesh, P. T., Copeland, C., Zhuang, Y., Wang, Y., Cho, Y., et al. (2024) · Gut · doi:10.1136/gutjnl-2023-331447 · Cited by 110 · see citing works
Guo, W., Li, Z., Anagnostopoulos, G., Kong, W. T., Zhang, S., Chakarov, S., Shin, A., Qian, J., Zhu, Y., Bai, W., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.08.016 · Cited by 109 · see citing works
FFA4/GPR120: Pharmacology and Therapeutic Opportunities
Milligan, G., Alvarez‐Curto, E., Hudson, B. D., Prihandoko, R., & Tobin, A. B. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.06.006 · Cited by 108 · cited 1× · see citing works
“FFAR1 and 4 are activated by medium-and long-chain free fatty acids and are putative targets for the treatment of type 2 diabetes by facilitating the secretion of glucose-stimulated insulin and the release of GLP-1 [203, 204].”
Kotsiliti, E., Leone, V., Schuehle, S., Govaere, O., Li, H., Wolf, M. J., Horvatic, H., Bierwirth, S., Hundertmark, J., Inverso, D., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.04.037 · Cited by 108 · cited 1× · see citing works
“Furthermore, genetic or therapeutic depletion of systemic or gastrointestinal B cells ameliorated T-cell-driven in fl ammation and fi brosis in MASH by inhibiting the IgA-FcR γ signaling axis on hepatic macrophages [170].”
Self-citationAbushamat, L. A., Shah, P. A., Eckel, R. H., Harrison, S. A., & Barb, D. (2024) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2024.01.032 · Cited by 97 · cited 2× · see citing works
“Many clinical trials have assessed the use of GLP-1R agonists for obesity and type 2 diabetes [183].”
The Multifaceted Roles of Macrophages in NAFLD Pathogenesis
Vonderlin, J., Chavakis, T., Sieweke, M., & Tacke, F. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.03.002 · Cited by 96 · cited 1× · see citing works
“Liver macrophages play a central role in MASLD, in fl uencing in fl ammation, fi brosis progression, and resolution [24, 25].”
Self-citationAspirin for Metabolic Dysfunction–Associated Steatotic Liver Disease Without Cirrhosis
Simon, T. G., Wilechansky, R. M., Stoyanova, S., Grossman, A., Dichtel, L. E., Lauer, G. M., Miller, K. K., Hoshida, Y., Corey, K. E., Loomba, R. S., et al. (2024) · JAMA · doi:10.1001/jama.2024.1215 · Cited by 96 · cited 1× · see citing works
“Interestingly, in a phase 2 randomized clinical trial (NCT04031729) of 80 individuals with MASLD, 6 months of daily low-dose aspirin signi fi cantly reduced hepatic fat quantity compared with placebo, but the fi ndings are preliminary and require con fi rmation in a larger population [210].”
Zhang, J., Wang, Y., Fan, M., Guan, Y., Zhang, W., Huang, F., Zhang, Z., Li, X., Yuan, B., Liu, W., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.05.008 · Cited by 94 · see citing works
Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair
De Ponti, F. F., Bujko, A., Liu, Z., Collins, P. J., Schuermans, S., Maueroder, C., Amstelveen, S., Thoné, T., Martens, L., McKendrick, J. G., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.002 · Cited by 94 · cited 1× · see citing works
“In addition to MASH, Trem2 + LAMs have been identi fi ed in various liver injury models, including acetaminophen (APAP)- and carbon tetrachloride (CCl 4 )- induced liver damage, where they play crucial roles in the ef fi cient clearance of dying cells [30].”
MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming
Mabire, M., Hegde, P., Hammoutene, A., Wan, J., Caër, C., Sayegh, R. A., Cadoux, M., Allaire, M., Weiss, E., Thibault-Sogorb, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37453-5 · Cited by 93 · cited 1× · see citing works
“Experimental evidence supports pro fi brogenic functions in chronically injured livers, and inhibiting MAIT cells promotes fi brosis regression via the induction of a repair phenotype in hepatic macrophages [93 – 95].”
Barb, D., Kalavalapalli, S., Leiva, E. G., Bril, F., Huot-Marchand, P., Dzen, L., Rosenberg, J. T., Junien, J., Broqua, P., Rocha, A. O., et al. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2024.12.045 · Cited by 91 · cited 1× · see citing works
“Another phase 2, single-center randomized trial (NCT03459079) also demonstrated that lani fi branor treatment signi fi cantly reduced hepatic steatosis and improved hepatic, muscle and adipose tissue insulin resistance in patients with type 2 diabetes and MASLD [202].”
Therapeutic opportunities for the treatment of NASH with genetically validated targets
Lindén, D., & Romeo, S. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.05.007 · Cited by 86 · cited 2× · see citing works
“Although the fi rst pharmacotherapeutic for MASLD and MASH, resmetirom, has been approved for clinical use [224], we expect more targeted treatments owing to the modest ef fi cacy of resmethrin [2].”
Shi, H., Wang, X., Li, F., Gerlach, B. D., Yurdagul, A., Moore, M. P., Zeldin, S., Zhang, H., Cai, B., Zheng, Z., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abp8309 · Cited by 85 · see citing works
Zhou, L., Qiu, X., Meng, Z., Liu, T., Chen, Z., Zhang, P., Kuang, H., Pan, T., Lu, Y., Qi, L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adk1866 · Cited by 81 · cited 1× · see citing works
“MS4A7, a Trem2 + MASH-associated macrophage-speci fi c pathogenic factor, exacerbated MASH progression in mice by inducing NLRP3 in fl ammasome activation via direct physical interaction, indicating that the LD-MS4A7-NLRP3 in fl ammasome axis is a key pathogenic driver of MASH progression [45].”
Self-citationγδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming
Torres‐Hernandez, A., Wang, W., Nikiforov, Y., Tejada, K., Torres, L., Kalabin, A., Adam, S., Wu, J., Lu, L., Chen, R., et al. (2020) · Hepatology · doi:10.1002/hep.30952 · Cited by 80 · cited 1× · see citing works
“…lymphocyte recruitment is mediated by distinct chemokine axes, including the CXCR6 ‒ CXCL16 pathway for natural killer T (NKT) cells, the CXCR3 ‒ CXCL9 ‒ CXCL10 pathway for in fl ammatory hepatic CXCR3 + Th17 (ihTh17) cells, and the CCR2 ‒ CCR5 signaling pathway for γδ T cells [74, 144, 146, 147].”
Mirea, A.-M., Toonen, E. J. M., van den Munckhof, I., Munsterman, I. D., Tjwa, E. T. T. L., Jaeger, M., Oosting, M., Schraa, K., Rutten, J. H. W., van der Graaf, M., et al. (2019) · Molecular Medicine · doi:10.1186/s10020-019-0084-3 · Cited by 77 · cited 1× · see citing works
“Consequently, the serum NE or NE-to-AAT ratio is commonly used as a biomarker to assess MASLD severity [71].”
Neutrophil-derived trail is a proinflammatory subtype of neutrophil-derived extracellular vesicles
Youn, Y.-J., Shrestha, S., Lee, Y.-B., et al. (2021) · Theranostics · doi:10.7150/thno.51756 · Cited by 77 · cited 1× · see citing works
“Neutrophils can produce various subtypes of EVs containing proin fl ammatory miRNAs or anti-in fl ammatory miRNAs [115].”
Huang, X., Yao, Y., Hou, X. S., Li, W., Rao, Y., Su, Y., Guo, Z., Ruan, X. Z., Li, D., & Chen, Y. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.03.006 · Cited by 74 · cited 1× · see citing works
“Moreover, macrophage-speci fi c Scap deletion ameliorated metain fl ammation and ectopic lipid deposition by promoting the release of in fl ammatory mediators by recruiting STING and tank-binding kinase 1 to the Golgi to activate the NF-κ B signaling pathway [107].”
Self-citationImmunomodulatory functions of FXR
Fiorucci, S., Zampella, A., Ricci, P., Distrutti, E., & Biagioli, M. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111650 · Cited by 73 · cited 1× · see citing works
“FXR, like other bile acid receptors, is also expressed in various innate immune cells, such as monocytes and macrophages, dendritic cells, and NK and NKT cells, thus modulating several aspects of innate immunity [194].”
Hwang, S., Wang, X.-L., Rodrigues, R., Ma, J., He, Y., Seo, W., Park, S., Kim, S.-J., Feng, D., & Gao, B. (2020) · Hepatology · doi:10.1002/hep.31390 · Cited by 67 · cited 1× · see citing works
“Hepatic overexpression of Cxcl1 and IL8 accelerated the transition from steatosis to MASH in HFD-fed mice and was associated with marked neutrophil in fi ltration and hepatocyte death [67].”
Self-citationRevisiting the Role of Natural Killer Cells in Non-Alcoholic Fatty Liver Disease
Martínez-Chantar, M. L., Delgado, T. C., & Beraza, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.640869 · Cited by 67 · cited 1× · see citing works
“However, in the context of obesity, NK cells may also support in fl ammation and alter metabolism via the induction of hepatic ER stress via osteopontin production and other mechanisms [89].”
Chandran, V. I., Wernberg, C. W., Lauridsen, M. M., Skytthe, M. K., Bendixen, S. M., Larsen, F. T., Hansen, C. D., Grønkjær, L. L., Siersbæk, M. S., Caterino, T. D., et al. (2022) · Hepatology · doi:10.1002/hep.32620 · Cited by 63 · cited 1× · see citing works
“…histologic features of NAFLD activity scores (NASs), such as steatosis, lobular in fl ammation, and ballooning, but only weakly with fi brosis stage, suggesting that sTrem2 in plasma may be a noninvasive biomarker that can rule-in or rule-out the presence of MASH with elevated liver stiffness [42].”
Dong, T., Hu, G., Fan, Z., Wang, H., Gao, Y., Wang, S., Xu, H., Yaffe, M. B., Heiden, M. G. V., Lv, G., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45167-5 · Cited by 63 · cited 1× · see citing works
“In addition to lipid metabolism in Kupffer cells, the activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells promotes glycolysis via the formation of complexes between β - arrestin 2 and key glycolytic enzymes, ultimately inhibiting in fl ammation and ameliorating MASLD [98].”
Zhang, Y., Wang, X., Lin, J., Liu, J., Wang, K., Nie, Q., Ye, C., Sun, L., Ma, Y., Qu, R., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.004 · Cited by 63 · cited 1× · see citing works
“Moreover, the gut microbiota is involved in the protective effects of time-restricted feeding (TRF) in MASLD via the production of 2-hydroxy-4-methylpentanoic acid (HMP), and oral supplementation with HMP alleviated in fl ammation and fi brosis in a MASH model [169].”
Envisioning how to advance the MASH field
Allen, A. M., Younossi, Z. M., Diehl, A. M., Charlton, M., & Lazarus, J. V. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00938-9 · Cited by 63 · cited 1× · see citing works
“Overnutrition with a poor-quality diet rich in glucose, high-fructose corn syrup and saturated fat leads to increased intrahepatic triglyceride levels, which are characteristic of MASLD, through multiple pathways [14].”
The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease
Engelmann, C., & Tacke, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020652 · Cited by 61 · cited 1× · see citing works
“Furthermore, hepatocyte senescence exacerbates this in fl ammatory cascade through the senescence-associated secretory phenotype (SASP) [139].”
Self-citationIL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis
Zhang, P., Liu, J., Lee, A. A., Tsaur, I., Ohira, M., Duong, V., Vo, N., Watari, K., Su, H., Kim, J. Y., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.08.012 · Cited by 60 · cited 1× · see citing works
“…that IL-22 resolved MASLD via the entry of IL-22R1 but not hepatic IL-22R1, as demonstrated by the fi nding that hepatocyte-speci fi c Il22r1 ablation still responded to IL-22 therapy, resulting in reduced body and liver weights, decreased liver damage, and decreased collagen accumulation [213].”
Yang, T., Qu, X., Wang, X., Xu, D., Sheng, M., Lin, Y., Ke, M., Song, C., Xia, Q., Jiang, L., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000638 · Cited by 59 · see citing works
IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis
Guan, Y., Peiffer, B., Feng, D., Parra, M. A., Wang, Y., Fu, Y., Shah, V. H., Cameron, A. M., Sun, Z., & Gao, B. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178616 · Cited by 59 · see citing works
Hepatocyte Adenosine Kinase Promotes Excessive Fat Deposition and Liver Inflammation
Li, H., Zheng, J., Xu, Q., Yang, Y., Zhou, J., Guo, X., Cai, Y., Cai, J. J., Xie, L., Awika, J. M., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.09.027 · Cited by 58 · cited 1× · see citing works
“These signals activate macrophages through the STING pathway, leading to the upregulation of the expression of proin fl amma-tory cytokines (IL-1 β , IL-6, IL-10, and TNF-α ) and increased expression of Ly6c2, a key marker of in fl ammatory monocyte recruitment [142].”
Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis
Liu, Q., Yu, J., Wang, L., Tang, Y., Zhou, Q., Ji, S., Wang, Y., SANTOS, L. V. D. S., Haeusler, R. A., Que, J., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.02.025 · Cited by 54 · cited 1× · see citing works
“For example, the expression of the immune regulator PU.1 is increased in the liver, primarily in macrophages, of obese mice and people, and pharmacologic PU.1 inhibition results in improved metabolic dysfunction in HFD-fed mice [18].”
Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease
Gwag, T., Mooli, R. G. R., Li, D., Lee, S., Lee, E. Y., & Wang, S. (2020) · JHEP Reports · doi:10.1016/j.jhepr.2020.100193 · Cited by 54 · see citing works
Hu, S., Li, R., Gong, D., Hu, P., Xu, J., Ai, Y., Zhao, X., Hu, C., Xu, M., Liu, C., et al. (2024) · Science Advances · doi:10.1126/sciadv.ado3141 · Cited by 54 · cited 1× · see citing works
“…via the reduction of cellular glucose levels via the inhibition of head box 1 (FoxO1)-mediated gluconeogenesis and the induction of free fatty acid (FFA) uptake by CD36, suggesting that ATF3 improves glucolipid metabolism in liver macrophages, ultimately protecting against MASH development [102].”
Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH
Itoh, M., Tamura, A., KANAI, S., Tanaka, M., Kanamori, Y., Shirakawa, I., Ito, A., Oka, Y., Hidaka, I., Takami, T., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20220681 · Cited by 53 · cited 2× · see citing works
“Treatment with β CD-PRX effectively mitigated MASH-related liver fi brosis by decreasing cholesterol accumulation and the pro fi brotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals without affecting hepatic and serum levels of cholesterol [62].”
Pang, J., Feng, J. N., Ling, W., & Jin, T. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.06.003 · Cited by 52 · cited 1× · see citing works
“The anti-in fl ammatory effects of GLP-1 in lung injury have also been summarized elsewhere [182].”
L’homme, L., Sermikli, B. P., Haas, J. T., Fleury, S., Quemener, S., Guinot, V., Barreby, E., Esser, N., Caiazzo, R. J., Verkindt, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51078-2 · Cited by 52 · cited 2× · see citing works
“However, as the disease progresses toward MASH, Gdf15 expression is induced in the liver, and hepatocytes, rather than macrophages, become its primary source [162].”
Spatial genomics: mapping human steatotic liver disease
Matchett, K. P., Paris, J., Teichmann, S. A., & Henderson, N. C. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00915-2 · Cited by 52 · cited 1× · see citing works
“However, analysis of these multimodal datasets is currently a major area of focus in the fi eld [215].”
Understanding the complex macrophage landscape in MASLD
Ponti, F. F. D., Liu, Z., & Scott, C. L. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101196 · Cited by 51 · cited 2× · see citing works
“Therefore, a range of conserved markers, including VSIG4, TIM4, and FOLR2, may help to distinguish EmKCs from MoKCs in MASLD [51].”
FGF-based drug discovery: advances and challenges
Chen, G., Chen, L., Li, X., & Mohammadi, M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01125-w · Cited by 51 · cited 1× · see citing works
“Fibroblast growth factor 21 (FGF21) is an endogenous liver-secreted hormone that has therapeutic potential for treating obesity, type 2 diabetes, and MASLD [190].”
Chen, J., Liang, B., Bian, D., Luo, Y., Yang, J., Li, Z., Zhuang, Z., Zang, S., & Shi, J. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.08.111 · Cited by 50 · cited 2× · see citing works
“Neutrophil elastase (NE), a serine protease secreted by neutrophils during in fl ammation via the degranulation process, plays a signi fi cant role in the pathogenesis and progression of MASH [70].”
Zheng, Y., Zhao, L., Xiong, Z., Huang, C., Yong, Q., Fang, D., Fu, Y., Gu, S., Chen, C., Li, J., et al. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0047 · Cited by 49 · cited 1× · see citing works
“Ursolic acid was shown to target secreted phosphoprotein 1 (SPP1) to regulate Th17 cells, thus improving immune in fl ammation in MASLD [20].”
Reporting discrepancy of alcohol intake affecting estimated prevalence of MetALD and ALD
Krag, A. A., Torp, N., Younossi, Z. M., et al. (2025) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(24)00427-8 · Cited by 49 · cited 1× · see citing works
“Owing to substantial underreporting and little recognition of the effect of alcohol on SLD, a more accurate prognose and effective management of SLD, addressing both metabolic and alcohol-related factors is crucial to appropriately diagnose, manage, and address the disease [222, 223].”
Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH
Boesch, M., Lindhorst, A., Feio‐Azevedo, R., Brescia, P., Silvestri, A., Lannoo, M., Deleus, E., Jaekers, J., Topal, H., Topal, B., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.10.039 · Cited by 48 · cited 4× · see citing works
“This loss coincided with the breakdown of vascular integrity in adipose tissue, a key event linked to the worsening of metabolic dysfunction and liver disease [155].”
InfluentialWei, X., Wu, D., Li, J., Wu, M., Li, Q., Che, Z., Cheng, X., Cheng, Q., Yin, F., Zhang, H., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.08.010 · Cited by 48 · cited 1× · see citing works
“Targeting β -arrestin 2 in myeloid cells may be a potential strategy for MASH treatment [100].”
Jeelani, I., Moon, J.-S., da Cunha, F. F., Nasamran, C., Jeon, S., Zhang, X.-H., Bandyopadhyay, G. K., Dobaczewska, K., Mikulski, Z., Hosseini, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0284 · Cited by 46 · cited 2× · see citing works
“…in controlling KC death in MASLD, as evidenced by the fact that HIF-2 α decreases lysosomal and phagocytic gene expression in KCs by inducing mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation [48].”
Self-citationXiang, L., Wang, G., Zhuang, Y., Luo, L., Yan, J., Zhang, H., Li, X., Xie, C., He, Q., Peng, Y., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.12.006 · Cited by 45 · see citing works
Dual roles of B lymphocytes in mouse models of diet-induced nonalcoholic fatty liver disease
Karl, M., Hasselwander, S., Zhou, Y., Reifenberg, G., Kim, Y. O., Park, K., Ridder, D. A., Wang, X., Seidel, E., Hövelmeyer, N., et al. (2022) · Hepatology · doi:10.1002/hep.32428 · Cited by 44 · cited 2× · see citing works
“Furthermore, another study demonstrated that B-cell-depleted mice were only partially protected from MASH, whereas B-cell-harboring but antibody-de fi cient IgMi mice were fully resistant to MASH [83].”
Shi, T., Malik, A., Hofe, A. Y. V., Matuschek, L., Mullen, M., Lages, C. S., Kudira, R., Singh, R., Zhang, W.-J., Setchell, K., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abi4354 · Cited by 44 · cited 1× · see citing works
“Although the immunoregulatory role of FXR in MASLD has not been clari fi ed, myeloid cells have been reported to mediate the hepatoprotective effects of pharmacological FXR agonists in sclerosing cholangitis [195].”
He, X., Wen, S., Tang, X., Wen, Z., Zhang, R. H., Li, S., Gao, R. B., Wang, J., Zhu, Y., Fang, D., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.03.011 · Cited by 44 · see citing works
Self-citationMicrobiota modulation by dietary oat beta-glucan prevents steatotic liver disease progression
Jaeger, J. W., Brandt, A., Gui, W., Yergaliyev, T., Hernández-Arriaga, A. M., Muthu, M. M., Edlund, K., Elashy, A., Molinaro, A., Möckel, D., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2023.100987 · Cited by 44 · cited 1× · see citing works
“…to decrease hepatic leukocyte in fi ltration, especially that of MoMFs, to dampen fi brosis development in diet-induced MASLD, which was associated with the reversal of diet-induced unfavorable changes in microbiota composition and a subsequent reduction in the translocation of TLR4 ligands [167].”
Herck, M. A. V., Vonghia, L., Kwanten, W. J., Julé, Y., Vanwolleghem, T., Ebo, D. G., Michielsen, P. P., Man, J. G. D., Gama, L., Winter, B. Y. D., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.04.010 · Cited by 43 · cited 1× · see citing works
“Importantly, in addition to macrophages, cytotoxic T cells in visceral adipose tissue (VAT) are considered critical regulators of MASH pathogenesis, which links adipose tissue in fl ammation to liver disease [163].”
Marinović, S., Lenartić, M., Mladenić, K., Šestan, M., Kavazović, I., Benić, A., Krapić, M., Rindlisbacher, L., Cokarić Brdovčak, M., Sparano, C., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.add1599 · Cited by 43 · cited 2× · see citing works
“IL-17A then induces hepatocytes to release chemokines, which recruit proin fl amma-tory myeloid cells into the liver [86].”
Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis
Fu, J., Liu, J., Wu, W., Chen, Y., Lu, G., Cao, Q., Meng, H., Tong, J., Zhu, J., Wang, X.-J., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.009 · Cited by 43 · cited 1× · see citing works
“…(EFHD2) was also signi fi cantly increased in hepatic macrophages/ monocytes from both patients and mice with MASH, which contributed to liver macrophage/monocyte reprogramming in MASH, whereas targeted EFHD2 inhibition via a hydrocarbon-stapled peptide effectively attenuated disease in mice [19].”
Self-citationSpatial dimension of macrophage heterogeneity in liver diseases
Guillot, A., & Tacke, F. (2023) · eGastroenterology · doi:10.1136/egastro-2023-000003 · Cited by 40 · cited 1× · see citing works
“Over the past decade, high-resolution methods, such as single-cell RNA sequencing (scRNAseq), single-nuclear RNA sequencing (snRNAseq), spatial transcriptomics, and spatial proteogenomics, have substantially increased our knowledge of different macrophage subsets [27].”
Self-citationThe steatotic liver disease burden paradox: unravelling the key role of alcohol
Torp, N., Israelsen, M. E., & Krag, A. A. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-01022-y · Cited by 39 · cited 2× · see citing works
“Of particular importance is the new category of individuals with MetALD, whose diagnosis of hepatic steatosis requires the presence of cardiometabolic risk factors (CMRFs) and daily alcohol intake between 20 – 50 g/day for women and between 30 – 60 g/day for men [11, 12].”
Hai, S., Li, X., Xie, E., Wu, W., Gao, Q., Yu, B., Hu, J., Xu, F., Zheng, X., Zhang, B., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000000985 · Cited by 38 · cited 1× · see citing works
“…aiming at ameliorating metabolic dysfunction-driven stress and injury in hepatocytes, these potential “ MASH therapies ” also inhibit the immune cell-mediated in fl ammatory response deletion of Il33 in mice ameliorated metabolic disorders, in fl ammation, and fi brosis associated with MASLD [165].”
Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives
Yan, M., Man, S., Ma, L., Guo, L., Huang, L., & Gao, W. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0315 · Cited by 37 · cited 1× · see citing works
“The “ multiple hit ” hypothesis has emerged as the dominant theory in recent years, indicating the collective impact of immunological mechanisms in the liver, intestines, and adipose tissue on the progression of MASLD [13].”
TREM2 macrophages mediate the beneficial effects of bariatric surgery against MASH
Fredrickson, G., Florczak, K. L., Barrow, F., Mahmud, S., DIETSCHE, K. B., Wang, H., Parthiban, P., Hakeem, A. N., Almutlaq, R. N., Adeyi, O. A., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000001098 · Cited by 37 · cited 2× · see citing works
“The regression livers were dominated by the LAM subpopulation [25, 41].”
Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice
Zou, Z., Liu, X., Yu, J., Ban, T., Zhang, Z., Wang, P., Huang, R., Zheng, F., Chang, Y., Peng, W., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.01.029 · Cited by 34 · cited 1× · see citing works
“…MASLD progression by ameliorating macrophage in fl ammation and coordinating macrophage actions on hepatocytes and HSCs to alleviate steatohepatitis and fi brosis [120]. miR-142a-3p is another miRNA that is essential for the functions of macrophages, whose secretion is regulated by Notch1 signaling.”
Gwag, T., Ma, E., Zhou, C., & Wang, S. (2022) · Liver International · doi:10.1111/liv.15182 · Cited by 33 · cited 1× · see citing works
“Another study con fi rmed that anti-CD47 antibody treatment did not affect mouse body weight, fat mass or liver steatosis but markedly reduced liver immune cell in fi ltration and fi brosis [137].”
Jiao, D., Sun, R., Ren, X., Wang, Y., Tian, P., Wang, Y., Yuan, D., Yue, X., Wu, Z., Li, C., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113211 · Cited by 33 · cited 1× · see citing works
“Additionally, lipid accumulation results in persistent NK cell dysfunction via histone hypoacetylation, and impaired functions are also observed in liver NK cells from HFD-fed mice [112].”
Use of artificial intelligence for liver diseases: A survey from the EASL congress 2024
Žigutytė, L., Sorz-Nechay, T., Clusmann, J., & Kather, J. N. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101209 · Cited by 33 · cited 1× · see citing works
“…opportunity to advance our understanding and management of MASLD, such as tabular medical data analysis, multiomics data analysis, the generation of synthetic patient data, enhancing the medical imaging fi eld for MASLD, and advancing personalized medicine approaches for MASLD [216, 217].”
Implications of innate immune sexual dimorphism for MASLD pathogenesis and treatment
Booijink, R. S., Ramachandran, P., & Bansal, R. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.05.004 · Cited by 32 · cited 1× · see citing works
“Interestingly, there are sex and sex differences in the prevalence of MASLD, and potential sex differences in innate immune cell types have been suggested to affect its development [17].”
Contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells
Hume, D. A., Offermanns, S., & Bonnavion, R. (2022) · Immunity · doi:10.1016/j.immuni.2022.06.010 · Cited by 31 · cited 1× · see citing works
“However, the identity of KC2 is currently debated in the fi eld because of its close transcriptomic pro fi le to that of liver sinusoidal endothelial cells (LSECs) [51, 53].”
Arvanitakis, K., Koufakis, T., Cholongitas, Ε., Francque, S., & Germanidis, G. S. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108811 · Cited by 31 · cited 1× · see citing works
“For example, the fi rst FDA-approved drug is an oral, liver-directed thyroid hormone receptor beta-selective agonist that plays a key role in regulating lipid metabolism, cholesterol synthesis, and fatty acid oxidation [173, 174].”
Ag-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice
Burtis, A. E. C., DeNicola, D. M. C., Ferguson, M. E., Santos, R. G., Pinilla, C., Kriss, M. S., Orlicky, D. J., Tamburini, B. A. J., Gillen, A. E., & Burchill, M. A. (2025) · Hepatology · doi:10.1097/hep.0000000000000971 · Cited by 30 · see citing works
Macrophages as Key Players during Adipose Tissue–Liver Crosstalk in Nonalcoholic Fatty Liver Disease
Korf, H., Boesch, M., Meelberghs, L., & der Merwe, V. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1687851 · Cited by 29 · cited 1× · see citing works
“…that obesity-related expansion of adipose tissue is associated with in fi ltration and activation of immune cells, especially adipose tissue macrophages (ATMs), which also contribute to MASLD progression since their proin fl ammatory cytokine repertoire leads to the adipose tissue secretome [159].”
Myeloid-specific blockade of Notch signaling ameliorates nonalcoholic fatty liver disease in mice
Ding, J., Xu, M. J., Du, W., Fang, Z., Xu, H., Liu, J., Song, P., Chen, X., Li, Z., Yue, Z., et al. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.80122 · Cited by 29 · see citing works
Chan, M. M., Daemen, S., Beals, J. W., Terekhova, M., Yang, B. Q., Fu, C. F., He, L., Park, A. C., Smith, G. I., Razani, B., et al. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100877 · Cited by 29 · cited 1× · see citing works
“However, EmKC death is not required for bone marrow-derived macrophage in fi ltration in MASLD [47].”
Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH
Woestemeier, A., Scognamiglio, P., Zhao, Y., Wagner, J., Muscate, F., Casar, C., Siracusa, F., Cortesi, F., Agalioti, T., Müller, S., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.153831 · Cited by 28 · cited 1× · see citing works
“Interestingly, among these cells, only those with a Th17 polarization state were enriched in patients with MASH-related fi brosis, providing the rationale to target CD4 + T cells with a Th17 polarization state to inhibit MASH-related fi brosis development [73].”
Pan, C., Liu, J., Gao, Y., Yang, M., Hu, H., Liu, C., Qian, M., Yuan, H.-Y., Yang, S., Zheng, M.-H., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.018 · Cited by 27 · cited 2× · see citing works
“Notably, CHRNA4 inhibition by lobeline prevents acetylcholine binding, thereby reducing immune cell recruitment and mitigating MASH progression [143].”
Yang, L., Hao, Y., Boeckmans, J., Rodrigues, R., & He, Y. (2023) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2023.108353 · Cited by 27 · cited 1× · see citing works
“Immunological studies on the pathogenesis of MASLD have revealed the key role of macrophages, whereas neutrophils have received less attention [218].”
Self-citationWade, H., Pan, K., Zhang, B., Zheng, W., & Su, Q. (2024) · eGastroenterology · doi:10.1136/egastro-2024-100115 · Cited by 27 · cited 1× · see citing works
“Moreover, the functions of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), have been widely studied in MASLD [113, 114].”
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Metabolic dysfunction and alcohol-associated liver disease (MetALD)
Gao, B., Arab, J. P., Liangpunsakul, S., Ding, W., Szabó, G., Mehal, W. Z., Wang, H., He, Y., Stärkel, P., Llorente, C., et al. (2025) · eGastroenterology · doi:10.1136/egastro-2025-100319 · Cited by 42 · see citing works
Self-citationZheng, H., Wu, K., Zheng, H., Chen, G., Lan, Y., Chen, S., Casu, G., Sechi, L. A., Wu, S., Vidili, G., et al. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101602 · Cited by 18 · see citing works
“…Neutrophil extracellular trap formation, M1 macrophages polarization, and T-cell imbalance contribute to hepatic inflammation and fibrosis, 38 while the same mechanisms also drive vascular inflammation, foam cell formation, and plaque instability, linking systemic immune activation to…”
Self-citationThe many pathways driving liver inflammation in MASH
Tilg, H., Adolph, T. E., Romeo, S., & Loomba, R. S. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.02.018 · Cited by 15 · see citing works
Youhanna, S., Taebnia, N., Liang, Y., Cheng, N., Wang, Y., Michel, M., & Lauschke, V. M. (2025) · Advanced Biology · doi:10.1002/adbi.202500337 · Cited by 9 · see citing works
Eid, R. A., Hamed, A. M., Elgendy, S. O., Orayj, K. M., Ibrahim, A. S., Hamied, A. M. A., Wahsh, E. A., Youssif, M., Rabea, H., Madney, Y. M., et al. (2025) · Metabolites · doi:10.3390/metabo16010025 · Cited by 9 · see citing works
Nutrigenomics of fat-soluble vitamins and micronutrients in hepatocyte lipotoxicity and MASLD
Migni, A., Bartolini, D., Ceccarini, M. R., Galli, C., Cavaliere, G., Garetto, S., Lucci, J., & Galli, F. (2026) · Progress in Lipid Research · doi:10.1016/j.plipres.2026.101380 · Cited by 8 · see citing works
Xu, Y., Li, Q., & Jiao, X. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1650677 · Cited by 7 · see citing works
“We will detail the evidence for this cycle and highlight how targeting its key nodes offers novel strategies for breaking the therapeutic bottleneck in MASLD (He et al., 2025).”
Immunometabolic integration in therapeutic strategies for managing MASLD
González-Serrano, S., Onoiu, A.-I., Camps, J., & Joven, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1693753 · Cited by 8 · see citing works
Liu, J., Wu, H., Zhou, L., Jin, Q., Ji, H., Hu, B., Wu, H., Chen, T., Wang, X., Hong, J., et al. (2026) · Metabolism · doi:10.1016/j.metabol.2025.156453 · Cited by 7 · see citing works
Chen, L.-L., Lu, Y.-J., Deng, A., Cao, J., Jin, F., Huang, H., Pan, F.-F., Liu, Y., Li, Y.-C., Tong, X., et al. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00794-8 · Cited by 5 · see citing works
“Some patients may eventually develop cirrhosis, and in advanced stages, HCC may arise as a severe complication, significantly impacting patients’ health and quality of life [155].”
Diambra, L. A., Sookoian, S. C., & Pirola, C. J. (2026) · Gut · doi:10.1136/gutjnl-2026-338674 · Cited by 4 · see citing works
Targeting Inflammation and Immune Regulation in Chronic Inflammation Associated Cancers
Rabiu, L., Chinn, M., Chen, F., Yerkinkazhina, Y., Tian, Y., & Zhu, W. (2026) · Cancer Science · doi:10.1111/cas.70360 · Cited by 4 · see citing works
“Chronic hepatic inflammation driven by lipotoxicity and oxidative stress promotes robust MDSC accumulation, leading to suppression of T-cell–mediated antitumor immunity [64].”
Li, Y. C., Hu, Y., He, Y. M., Yang, Y., Xue, D., Xue, E., Jia, J., Zhang, W., & Wang, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1793092 · Cited by 4 · see citing works
“This shift does not imply that metabolites directly determine immune cell fate; rather, they are more likely to constrain metabolic fl exibility required for transitions between distinct functional states by reshaping the relative balance among intracellular metabolic pathways (43).”
Self-citationHu, K., Liu, S., Sheng, S., Zhang, S., Li, B., Sun, B., & Xia, A. (2026) · iLiver · doi:10.1016/j.iliver.2026.100234 · Cited by 5 · see citing works
“100 Recent integrated spatial and single-cell multi-omics investigations in human MASLD livers have identified MITF as a pivotal regulator of the lipid-handling capacity of LAMs, directly controlling their lipid metabolic pathways.”
Wiszniewski, M., Mori, D., Puch, S. I. S., Calejman, C. M., Cymeryng, C. B., & Repetto, E. M. (2025) · Biology · doi:10.3390/biology14081058 · Cited by 5 · see citing works
“Taking this into account, influencing liver inflammation by the inhibition of pro-inflammatory pathways or by stimulating anti-inflammatory pathways seems to be a promising therapeutic approach for MASH treatment [20].”
Herdiana, Y. (2025) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s562536 · Cited by 4 · see citing works
“HCC represents the terminal stage of MASLD progression, with emerging evidence implicating immune regulation in the transition from MASH to HCC. 7 Management of MASLD currently remains a significant clinical challenge.”
The Role of Neutrophils in Non-Alcoholic Fatty Liver Disease: Mechanisms and Clinical Significance
Zhang, F., & Li, W. (2026) · Journal of Inflammation Research · doi:10.2147/jir.s585447 · Cited by 3 · see citing works
Perl, A., & Banki, K. (2026) · Nature Reviews Rheumatology · doi:10.1038/s41584-026-01421-2 · Cited by 3 · see citing works
“Alterations in lipid metabolism associated with MASLD can promote systemic inflammation and immune dysregulation 197 .”
Liu, Z., Zhou, B., Fang, J., Yu, Y., Jiang, X., Chen, X.-Y., Wang, W., Fu, X.-Y., Xia, J.-L., Liu, B.-J., et al. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1673662 · Cited by 3 · see citing works
“Metabolic dysfunction-associated steatotic liver disease (MASLD), which aected approximately 30% of adults worldwide (13), is a significant metabolic disorder whose prevalence mirrors the increasing prevalence of obesity and T2DM.”
Kumar, G., Shah, Y. R., Shahzad, A., Jameel, K., Guevara-Lazo, D., Khan, N. A., Dahiya, D. S., Gangwani, M. K., Ravichandran, R., Patel, R. J., et al. (2025) · World Journal of Hepatology · doi:10.4254/wjh.v17.i11.111576 · Cited by 2 · see citing works
Lacerda, R. R. E., Barra, N. G., Conn, M. O., Zada, D. K., Robin, N., Fang, H., Marko, D. M., Punde, N. M., Kalyan, S., Gunn, H., et al. (2026) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00488.2025 · Cited by 2 · see citing works
N 6 ‐Methyladenosine (m 6 A) in Liver Disease: Pathogenic Mechanisms and Therapeutic Potential
Chen, Y., Ya, R., Zhang, Z., Dong, S., Park, S. H., Seo, W., & He, Y. (2026) · iNew Medicine · doi:10.1002/inm3.70036 · Cited by 2 · see citing works
Self-citationComparison and Characteristics of MASLD Mouse Models
Wei, L., 高春辰, & Qin, H. (2026) · Biomedicines · doi:10.3390/biomedicines14040895 · Cited by 3 · see citing works
“…signaling axis in KCs, the NLRP3 inflammasome, and related molecules such as MyD88, iNOS, and HMGB1—drive hepatic inflammation, steatosis, and fibrosis by regulating pro-inflammatory cytokine release; correspondingly, gene knockout can alleviate MASLD-related pathological alterations [102,103].”
Alhawiti, N. M. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1728096 · Cited by 3 · see citing works
“In mouse models of MASH, treatment with aspirin or clopidogrel, a P2Y12 receptor antagonist, resulted in decreased serum ALT levels, reduced hepatic infiltration of immune cells, and lower expression of profibrotic markers such as α -SMA and collagen type I (134).”
Zhao, L., Xu, S., Qiao, S., Wang, Z., 王勝嵐, Liu, C., Zhang, S., Wang, P., Sun, X., Li, S., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02704-6 · Cited by 2 · see citing works
“35,36 This process activates Kupffer cells and promotes recruitment of myeloid immune populations; if unresolved, subsequent engagement of adaptive immunity contributes to the development of MASLD.”
Chen, L., Chen, Y., Zhao, M., Yang, X., Sutte, K., Lu, M., Chen, J., Zheng, X., Yang, D., & Liu, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1814879 · Cited by 1 · see citing works
“In addition to competing for survival signals like CSF-1 (9, 33, 34), in fi ltrating monocytes actively replace embryonic KCs (EmKCs) during injury (35 – 37).”
Self-citationDissecting the immune pathogenesis of HBV-ACLF through single-cell multimodal analysis
Tacke, F., & Trebicka, J. (2025) · Gut · doi:10.1136/gutjnl-2025-336545 · Cited by 1 · see citing works
“11 Such interventions need to be tailored to patient characteristics”
Self-citationLiver immunology: new insights from cutting-edge technologies
Guillot, A., & Gao, B. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01342-2 · Cited by 1 · see citing works
“1B) [5 – 7].”
Metabolic Liver Disease Beyond the Liver
Gastaldelli, A., Tacke, F., & Holleboom, A. G. (2026) · Clinics in Liver Disease · doi:10.1016/j.cld.2025.12.003 · Cited by 1 · see citing works
Self-citationDaixie recipe ameliorates diet-induced MASH in mice via activating PI3K/AKT and Keap1/Nrf2 signaling
He, X., You, J., Deng, Y., Hu, Y., Qi, S., Li, Q., Yang, Y., Qu, X., Shao, Y., Fu, X., et al. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1772033 · Cited by 1 · see citing works
“In fl ammatory responses are a key driver of MASH progression, originating not only from the activation of Kupffer cells and macrophages but also from hepatocyte-derived in fl ammatory mediators (27, 28).”
Self-citationSia, J., Lee, B., & Oon, H. H. B. (2026) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-026-09152-8 · Cited by 1 · see citing works
Xue, L., Wang, X., & Mao, J. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1808135 · Cited by 1 · see citing works
Gou, Z.-X., Li, N.-W., Yao, J.-Y., & Wang, Y. (2026) · International Journal of Nanomedicine · doi:10.2147/ijn.s597554 · Cited by 1 · see citing works
Guo, Y., Ma, Q., Guo, Z., Chu, J., Wu, N., & Yajuan, Q. I. (2026) · Life Sciences · doi:10.1016/j.lfs.2026.124534 · Cited by 1 · see citing works
Li, X., Jin, K., Fang, J., Ma, X., He, J., Lu, A., Jia, Z., & Shi, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1835197 · Cited by 3 · see citing works
“In murine hepatic tissue, GLP-1R is present on gd T cells, where GLP-1 inhibits their in fl ammatory activity to reduce hepatic in fl ammation (181).”
Shen, K., Zhao, J., Li, K., Xu, L., & Wu, H. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1874886 · Cited by 1 · see citing works
“Chronic low-grade in fl ammation is another important feature of MASLD (14).”
Ma, Y., Gao, X., Wang, J., Li, L., Huang, Z., & Li, F. (2026) · Chemical Biology & Drug Design · doi:10.1111/cbdd.70371 · Cited by 1 · see citing works
Meng, Z., Zhou, T., Gou, J., Jiang, C., Li, B., Zhou, H., Liu, J., Feng, Q., & Wen, L. (2025) · Research Square · doi:10.21203/rs.3.rs-7551051/v1 · Cited by 1 · see citing works
Onoiu, A.-I., Murray, L., Gerardin, Y., Singh, G., Egger, R., González-Serrano, S., Cambra-Cortés, V., Jiménez-Franco, A., Guilarte, C., Parada, D., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-8725050/v1 · Cited by 1 · see citing works
Yan, C., Han, S., Chen, Q., He, J., Wang, T., Shen, X., & Gong, X. (2025) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2025.104208
Huang, J.-W., Man, N., Wang, H., Ai, X., Wei, D.-L., & Dai, Y. (2025) · Hepatic Medicine Evidence and Research · doi:10.2147/hmer.s562237
Guo, S.-Q., Li, Z.-R., Han, Z., Ge, Y., Shi, H., Zheng, Y., Tan, W., Xing, C., Li, Z.-C., Li, Y., et al. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s546860
Frietze, K. K., Brown, A., Das, D., Franks, R. G., Jagadeesan, P., & Nickels, J. T. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111212
Chen, Q., Liu, L., Feng, J., et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-43311-3
“Accumulating evidence indicates that macrophages and CD8 ⁺ T cells infiltrate extensively during MASLD progression and contribute to the maintenance of chronic inflammation and disease advancement 38 .”
Hemati, H., Blanton, M. B., Rutt, L. N., Keiran, N., Geron, R. D., Lima, F., McCullough, R. L., & Messaoudi, I. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1783132 · Cited by 1 · see citing works
The biliary tree: A new frontier in mucosal immunology?
Yin, G., Chouik, Y., Hao, Y.-W., Kohlhepp, M., & Guillot, A. (2026) · Mucosal Immunology · doi:10.1016/j.mucimm.2026.04.006
Kotlyarov, S. N. (2026) · World Journal of Hepatology · doi:10.4254/wjh.v18.i4.116689
ANXA1-FPR1 signaling in myeloid cells drives MASH by elevating S100A4/A11
Yang, S., Qian, S., Yang, L., He, Y., Ge, S., Fu, X., Dong, S., Ya, R., Chen, Y., Ma, N., et al. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.101869
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Adipose tissue inflammation: a main driver of metabolic dysfunction-associated steatohepatitis
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Integrative Functional Nutrition in Metabolic-Associated Fatty Liver Disease
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- Authors
- He, Y., Chen, Y., Qian, S., van Der Merwe, S., Dhar, D., Brenner, D. A., & Tacke, F.
- Affiliations
- Chinese Academy of Sciences (CN)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- He, Yong
- Tacke, Frank
- Venue
- Cellular & Molecular Immunology
- Published
- 2025-06-10
- Volume
- 22
- Issue
- 10
- Pages
- 1159-1177
- ISSN
- 1672-7681 (ISSN-L)
- 2042-0226
- PMC
- PMC12480724
- OpenAlex
- W4411162672
- Semantic Scholar
- 7f2f36cf67705164236941f4c20e7acd81779cf2
- Cited by
- 81
- References
- 226
- Citations by year
- 2026: 63 · 2025: 18
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cellular and Molecular Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health and Human Services (R01DK133930, RO1DK137061)
- Deutsche Forschungsgemeinschaft (SFB 1382, DFGTa434/8‐1, Ta434/8‐1, 403224013)
- National Natural Science Foundation of China (82270601, 403224013)
- National Institutes of Health
- National Key Research and Development Program of China (2024ZD0530604, 2023YFA1800804)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK137061, R01DK133930)
- 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
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, immunopathogenesis, liver inflammation, immunomodulatory therapy, resmetirom, incretin mimetics, liver fibrosis, genetic susceptibility, overnutrition
- MeSH terms
- Animals, Humans, Liver, Immunomodulation, Non-alcoholic Fatty Liver Disease
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