Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023). International consensus statement providing the new nomenclature for MASLD.
Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980). The initial publication describing the disease NASH.
Huang, D. Q., El-Serag, H. B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18, 223–238 (2021).
Younossi, Z. M., Kalligeros, M. & Henry, L. Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clin. Mol. Hepatol. 31, S32–S50 (2025).
Zhou, X. D. et al. Global burden of disease attributable to metabolic risk factors in adolescents and young adults aged 15-39, 1990-2021. Clin. Nutr. 43, 391–404 (2024).
Stroes, A. R., Vos, M., Benninga, M. A. & Koot, B. G. P. Pediatric MASLD: current understanding and practical approach. Eur. J. Pediatr. 184, 29 (2024).
Lefere, S. et al. Update in clinical science: MASLD in children and adolescents. J. Hepatol. https://doi.org/10.1016/j.jhep.2026.02.016 (2026).
Ding, J. et al. Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Sci. Transl. Med. 16, eadh9940 (2024).
Jamialahmadi, O. et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease. Nat. Med. 30, 3614–3623 (2024). The authors identified that MASLD comprises of at least two subgroups: liver-centric and cardiometabolic centric.
Raverdy, V. et al. Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease. Nat. Med. 30, 3624–3633 (2024). The authors identified MASLD as comprising at least 2 subgroups: liver-centric and cardiometabolic centric.
Le, P. et al. Estimated burden of metabolic dysfunction-associated steatotic liver disease in US adults, 2020 to 2050. JAMA Netw. Open 8, e2454707 (2025).
McPherson, S. et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol. 62, 1148–1155 (2015).
Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005). This study introduced the histopathological NAS for the assessment of NASH/MASH.
Huang, D. Q. et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 34, 969–977 (2022). The authors identified that NASH/MASH is the fastest growing cause of liver cancer in the past decade.
Vitale, A. et al. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database. Gut 72, 141–152 (2023).
Koh, J. H. et al. NASH is the leading cause of hepatocellular carcinoma in liver transplant candidates. Clin. Gastroenterol. Hepatol. 22, 197–199 (2024).
Hall, K. D. et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 30, 67–77 (2019).
Karlsen, T. H. et al. The EASL-Lancet Commission on liver health in Europe: prevention, case-finding, and early diagnosis to reduce liver-related mortality. Lancet 403, 1522–1524 (2024).
Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).
Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836–1846 (2010).
Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014). The authors demonstrated that CD8+ T cells and natural killer T cells drive liver injury, steatosis and liver cancer by modulating fatty acid metabolism in hepatocytes.
Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161–175 (2016). The authors showed that IL-17A secreted by TH17 cells drive adipose tissue insulin resistance, MASH and HCC.
Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019). The authors demonstrated that intrahepatic platelets drive MASH and MASH-HCC and APT can attenuate this process.
Rappez, L. et al. SpaceM reveals metabolic states of single cells. Nat. Methods 18, 799–805 (2021).
Byrne, C. D., Armandi, A., Pellegrinelli, V., Vidal-Puig, A. & Bugianesi, E. Μetabolic dysfunction-associated steatotic liver disease: a condition of heterogeneous metabolic risk factors, mechanisms and comorbidities requiring holistic treatment. Nat. Rev. Gastroenterol. Hepatol. 22, 314–328 (2025).
Targher, G., Byrne, C. D. & Tilg, H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 73, 691–702 (2024).
Ertle, J. et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 128, 2436–2443 (2011).
Piscaglia, F. et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 63, 827–838 (2016).
Targher, G., Valenti, L. & Byrne, C. D. Metabolic dysfunction-associated steatotic liver disease. N. Engl. J. Med. 393, 683–698 (2025).
Letouzé, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).
Petersen, K. F. et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl Acad. Sci. USA 104, 12587–12594 (2007).
Roden, M. & Shulman, G. I. The integrative biology of type 2 diabetes. Nature 576, 51–60 (2019).
Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).
Anstee, Q. M. et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. J. Hepatol. 73, 505–515 (2020).
Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008). The initial paper that identified the PNPLA3 risk variant contributing to MASLD progression.
Mancina, R. M. et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).
Bianco, C. et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J. Hepatol. 74, 775–782 (2021).
De Vincentis, A. et al. A polygenic risk score to refine risk stratification and prediction for severe liver disease by clinical fibrosis scores. Clin. Gastroenterol. Hepatol. 20, 658–673 (2022).
He, S. et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 285, 6706–6715 (2010).
Smagris, E. et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108–118 (2015).
Li, J. Z. et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130–4144 (2012).
Basantani, M. K. et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J. Lipid Res. 52, 318–329 (2011).
BasuRay, S., Smagris, E., Cohen, J. C. & Hobbs, H. H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111–1124 (2017).
Sherman, D. J. et al. PNPLA3-I148M is a neomorph that interferes with two primary hepatic triglyceride clearance pathways. Cell Rep. 44, 116371 (2025).
Wang, Y. et al. PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. J. Hepatol. 82, 871–881 (2025).
Wang, Y., Kory, N., BasuRay, S., Cohen, J. C. & Hobbs, H. H. PNPLA3, CGI-58, and inhibition of hepatic triglyceride hydrolysis in mice. Hepatology 69, 2427–2441 (2019).
Johnson, S. M. et al. PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein. Nat. Commun. 15, 4847 (2024).
Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276–1282 (2012).
Luukkonen, P. K. et al. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metab. 35, 1887–1896 (2023).
Yki-Järvinen, H. & Luukkonen, P. K. Function of PNPLA3 I148M—lessons from in vivo studies in humans. Liver Int. 45, e70047 (2025).
Caon, E. et al. Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models. J. Hepatol. 80, 941–956 (2024).
Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).
Liu, Y. L. et al. Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61, 75–81 (2014).
Rosso, C. et al. Impact of PNPLA3 rs738409 polymorphism on the development of liver-related events in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 21, 3314–3321 (2023).
Fabbrini, E. et al. Phase 1 trials of PNPLA3 siRNA in I148M homozygous patients with MAFLD. N. Engl. J. Med. 391, 475–476 (2024).
Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).
Borén, J. et al. Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans. JCI Insight https://doi.org/10.1172/jci.insight.144079 (2020).
Ehrhardt, N. et al. Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Hum. Mol. Genet. 26, 2719–2731 (2017).
Prill, S. et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci. Rep. 9, 11585 (2019).
Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).
Holmen, O. L. et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 46, 345–351 (2014).
Beer, N. L. et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18, 4081–4088 (2009).
Ma, Y. et al. 17-β hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology 69, 1504–1519 (2019).
Rendel, M. D. et al. The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD. Med https://doi.org/10.1016/j.medj.2024.04.010 (2024).
Pinyol, R. et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J. Hepatol. 75, 865–878 (2021).
Chotiprasidhi, P., Sato-Espinoza, A. K. & Wangensteen, K. J. Germline Genetic Associations for Hepatobiliary Cancers. Cell. Mol. Gastroenterol. Hepatol. 17, 623–638 (2024).
Mezina, A. et al. Multigene panel testing in individuals with hepatocellular carcinoma identifies pathogenic germline variants. JCO Precis. Oncol. https://doi.org/10.1200/po.21.00079 (2021).
Rothman, D. L. et al. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc. Natl Acad. Sci. USA 92, 983–987 (1995).
Cline, G. W. et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Med. 341, 240–246 (1999).
Shulman, G. I. et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med. 322, 223–228 (1990).
Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).
Griffin, M. E. et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48, 1270–1274 (1999).
Lyu, K. et al. A membrane-bound diacylglycerol species induces PKCЄ-mediated hepatic insulin resistance. Cell Metab. 32, 654–664 (2020).
Song, J. D. et al. Dissociation of muscle insulin resistance from alterations in mitochondrial substrate preference. Cell Metab. 32, 726–735 (2020).
Gassaway, B. M. et al. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proc. Natl Acad. Sci. USA 115, E8996–E9005 (2018).
Dresner, A. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103, 253–259 (1999).
Clerk, L. H. et al. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes 55, 1436–1442 (2006).
Mayerson, A. B. et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51, 797–802 (2002).
Perseghin, G. et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N. Engl. J. Med. 335, 1357–1362 (1996).
Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608 (2005).
Petersen, K. F. et al. Mechanism of troglitazone action in type 2 diabetes. Diabetes 49, 827–831 (2000).
Petersen, K. F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).
Rabøl, R., Petersen, K. F., Dufour, S., Flannery, C. & Shulman, G. I. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc. Natl Acad. Sci. USA 108, 13705–13709 (2011).
Shulman, G. I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371, 2237–2238 (2014).
Samuel, V. T. et al. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117, 739–745 (2007).
Ter Horst, K. W. et al. Hepatic diacylglycerol-associated protein kinase Cε translocation links hepatic steatosis to hepatic insulin resistance in humans. Cell Rep. 19, 1997–2004 (2017).
Li, X. et al. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice. Proc. Natl Acad. Sci. USA 117, 32584–32593 (2020).
Perry, R. J. et al. Mechanisms by which a very-low-calorie diet reverses hyperglycemia in a rat model of type 2 diabetes. Cell Metab. 27, 210–217 (2018).
Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L. & Shulman, G. I. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347, 1253–1256 (2015). The authors showed that a novel formulation of a mitochondrial uncoupler reverses diabetes and steatohepatitis.
Weiss, R. et al. Low adiponectin levels in adolescent obesity: a marker of increased intramyocellular lipid accumulation. J. Clin. Endocrinol. Metab. 88, 2014–2018 (2003).
Matsumoto, M. et al. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int. J. Exp. Pathol. 94, 93–103 (2013).
Meakin, P. J. et al. Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. Mol. Cell. Biol. 34, 3305–3320 (2014).
Abulizi, A. et al. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. J. Lipid Res. 61, 1565–1576 (2020).
Brown, J. M. et al. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J. Lipid Res. 51, 3306–3315 (2010).
Sun, Z. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934–942 (2012).
Leamy, A. K., Egnatchik, R. A. & Young, J. D. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid Res. 52, 165–174 (2013).
Choi, C. S. et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J. Biol. Chem. 282, 22678–22688 (2007).
Xu, W. et al. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptor(T1150) phosphorylation pathway. Cell Rep. 43, 114746 (2024).
Jornayvaz, F. R. et al. Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc. Natl Acad. Sci. USA 108, 5748–5752 (2011).
Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745–758 (2015).
Vatner, D. F. et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc. Natl Acad. Sci. USA 112, 1143–1148 (2015).
Barrows, B. R. & Parks, E. J. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J. Clin. Endocrinol. Metab. 91, 1446–1452 (2006).
Ter Horst, K. W. et al. Hepatic insulin resistance is not pathway selective in humans with nonalcoholic fatty liver disease. Diabetes Care 44, 489–498 (2021).
Nier, A. et al. Adipokines and endotoxemia correlate with hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Nutrients https://doi.org/10.3390/nu12030699 (2020).
Kaser, S. et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut 54, 117–121 (2005).
Begriche, K., Massart, J., Robin, M. A., Bonnet, F. & Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58, 1497–1507 (2013).
Moore, M. P. et al. Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD. Hepatology 76, 1452–1465 (2022).
Rector, R. S. et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J. Hepatol. 52, 727–736 (2010).
Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).
Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).
Sunny, N. E., Parks, E. J., Browning, J. D. & Burgess, S. C. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14, 804–810 (2011).
Kotronen, A. et al. Liver fat and lipid oxidation in humans. Liver Int. 29, 1439–1446 (2009).
Petersen, K. F., Befroy, D. E., Dufour, S., Rothman, D. L. & Shulman, G. I. Assessment of hepatic mitochondrial oxidation and pyruvate cycling in NAFLD by 13C magnetic resonance spectroscopy. Cell Metab. 24, 167–171 (2016).
Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021). Phase 2 clinical trial showing the effectiveness of pan-PPAR agonization in MASH.
Harrison, S. A. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390, 497–509 (2024).
Harrison, S. A. et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 29, 2919–2928 (2023).
Goedeke, L. et al. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aay0284 (2019).
Noureddin, M. et al. Safety and efficacy of once-daily HU6 versus placebo in people with non-alcoholic fatty liver disease and high BMI: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol. Hepatol. 8, 1094–1105 (2023).
Petersen, K. F., Dufour, S., Mehal, W. Z. & Shulman, G. I. Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease. Cell Metab. https://doi.org/10.1016/j.cmet.2024.07.023 (2024).
Befroy, D. E. et al. Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nat. Med. 20, 98–102 (2014).
Pandey, A. et al. Novel controlled metabolic accelerator for obesity-related HFpEF: the HuMAIN-HFpEF randomized clinical trial. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2025.0103 (2025).
Siddle, M. et al. Mechanistic insights into the liver-brain axis during chronic liver disease. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-025-01142-z (2025).
Carty, J. R. E. et al. Amygdala-liver signalling orchestrates glycaemic responses to stress. Nature 646, 697–706 (2025).
Hwang, J. et al. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice. Nat. Commun. 16, 991 (2025).
Rose, J. P. et al. FGF21 reverses MASH through coordinated actions on the CNS and liver. Cell Metab. 37, 1515–1529 (2025). The authors found that the benefits of FGF21 signalling in MASH are mediated through both hepatic and CNS effects.
Kang, D. et al. Perceived stress and non-alcoholic fatty liver disease in apparently healthy men and women. Sci. Rep. 10, 38 (2020).
Kim, D. et al. Depression is associated with non-alcoholic fatty liver disease among adults in the United States. Aliment Pharmacol. Ther. 50, 590–598 (2019).
Youssef, N. A. et al. Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease. Liver Int. 33, 1062–1070 (2013).
Kullmann, S. et al. Brain insulin sensitivity is linked to adiposity and body fat distribution. Nat. Commun. 11, 1841 (2020).
Kullmann, S. et al. A short-term, high-caloric diet has prolonged effects on brain insulin action in men. Nat. Metab. 7, 469–477 (2025).
Patke, A., Young, M. W. & Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol. 21, 67–84 (2020).
Huang, H., Liu, Z., Xie, J. & Xu, C. Association between night shift work and NAFLD: a prospective analysis of 281,280 UK Biobank participants. BMC Publ. Health 23, 1282 (2023).
Singh, A. et al. Night shift-induced circadian disruption: links to initiation of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and risk of hepatic cancer. Hepatoma Res. https://doi.org/10.20517/2394-5079.2024.88 (2024).
Lee, Y. & Lee, W. Shift work and non-alcoholic fatty liver disease in young, healthy workers. Sci. Rep. 14, 19367 (2024).
Marjot, T. et al. Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night. Cell Metab. 38, 474–492 (2026). This study showed that human MASLD is a diurnal disease with lower insulin secretion and increased insulin resistance and DNL during the nighttime.
Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).
Sinturel, F. et al. Diurnal oscillations in liver mass and cell size accompany ribosome assembly cycles. Cell 169, 651–663 (2017).
Kettner, N. M. et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 30, 909–924 (2016). The authors demonstrated that circadian disruption alters hepatic metabolism driving steatosis and liver cancer in mice.
Padilla, J. et al. Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model. J. Hepatol. 80, 282–292 (2024).
Chaix, A., Lin, T., Le, H. D., Chang, M. W. & Panda, S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 29, 303–319 (2019).
Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).
Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586–591 (2020).
Sakuma, I. et al. Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition. Proc. Natl Acad. Sci. USA 120, e2312666120 (2023).
Sakuma, I. et al. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction-associated steatohepatitis. Proc. Natl Acad. Sci. USA 122, e2502978122 (2025).
Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).
Slusher, A. L. et al. ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis. J. Clin. Invest. https://doi.org/10.1172/jci184740 (2025).
Ajoolabady, A. et al. Endoplasmic reticulum stress in liver diseases. Hepatology 77, 619–639 (2023).
Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).
Li, X. et al. Activated ATF6α is a hepatic tumour driver restricting immunosurveillance. Nature https://doi.org/10.1038/s41586-025-10036-8 (2026). The authors showed that chronic, unrestrained ER stress drives liver injury and liver cancer.
Henkel, A. S. Unfolded protein response sensors in hepatic lipid metabolism and nonalcoholic fatty liver disease. Semin. Liver Dis. 38, 320–332 (2018).
Kim, J. Y. et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175, 133–145 (2018).
Hazari, Y. et al. Targeting the ER stress sensor IRE1 protects the liver from fibrosis through the downregulation of the proteostasis factor P4HB/PDIA1. Hepatology https://doi.org/10.1097/hep.0000000000001335 (2025).
Boslem, E. et al. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. Sci. Adv. 9, eadh0831 (2023).
Govaere, O. et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aba4448 (2020). This study conducted an unbiased transcriptomic analyses across the MASLD spectrum and identified distinct signatures for steatohepatitis and fibrosis.
Patel, S. et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 29, 707–718 (2019).
Kim, J. et al. TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response. Nat. Metab. 3, 410–427 (2021).
Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020).
Seedorf, K. et al. Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice. JHEP Rep. 5, 100651 (2023).
Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).
Komatsu, M. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213–223 (2010).
Jara, M. et al. Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis. Nat. Med. https://doi.org/10.1038/s41591-025-03799-0 (2025).
Arab, J. P., Karpen, S. J., Dawson, P. A., Arrese, M. & Trauner, M. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).
Govaere, O. et al. Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment. Biochem. Pharmacol. https://doi.org/10.1016/j.bcp.2024.116249 (2024).
Umemura, A. et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935–948 (2016).
Kwon, J., Kim, J. & Kim, K. I. Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases. Anim. Cells Syst. 27, 29–37 (2023).
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
Steinberg, G. R. & Hardie, D. G. New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 24, 255–272 (2023).
Umemura, A. et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 20, 133–144 (2014).
Uehara, K. et al. Activation of liver mTORC1 protects against NASH via dual regulation of VLDL-TAG secretion and de novo lipogenesis. Cell. Mol. Gastroenterol. Hepatol. 13, 1625–1647 (2022).
Gosis, B. S. et al. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1. Science 376, eabf8271 (2022).
Bae, E. J. et al. Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance. J. Biol. Chem. 287, 18769–18780 (2012).
Lluch, A. et al. A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis. JCI Insight https://doi.org/10.1172/jci.insight.150461 (2022).
Garcia, D. et al. Genetic liver-specific AMPK activation protects against diet-induced obesity and NAFLD. Cell Rep. 26, 192–208 (2019).
Woods, A. et al. Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep. 18, 3043–3051 (2017).
Zhao, P. et al. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367, 652–660 (2020).
Amin, N. B. et al. Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study. BMJ Open 12, e056159 (2022).
Wong, V. W. et al. Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study. Lancet Gastroenterol. Hepatol. https://doi.org/10.1016/s2468-1253(25)00128-1 (2025).
Cusi, K. et al. Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Gastroenterol. Hepatol. 6, 889–902 (2021).
Gallage, S. et al. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1. Cell Metab. 36, 1371–1393 (2024). The authors demonstrated that a 5:2 intermittent fasting regimen can improve MASH and blunt subsequent liver cancer development via hepatic PPARα and PCK1.
Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572–579 (2012).
Pu, W. et al. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat. Genet. 55, 651–664 (2023).
Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354 (2017).
Gupta, V., Sehrawat, T. S., Pinzani, M. & Strazzabosco, M. Portal fibrosis and the ductular reaction: pathophysiological role in the progression of liver disease and translational opportunities. Gastroenterology https://doi.org/10.1053/j.gastro.2024.07.044 (2024).
Algueró-Nadal, A. et al. Steatotic liver disease induces YAP/TAZ-driven cell competition that can suppress tumor initiation. J. Hepatol. https://doi.org/10.1016/j.jhep.2025.06.002 (2025).
Yu, J. et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abe1692 (2021).
Gribben, C. et al. Acquisition of epithelial plasticity in human chronic liver disease. Nature 630, 166–173 (2024).
Du, K., Umbaugh, D. S., Ren, N. & Diehl, A. M. Cellular senescence in liver diseases: from molecular drivers to therapeutic targeting. J. Hepatol. 84, 194–212 (2026).
Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).
Gallage, S. et al. Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome. Nat. Aging https://doi.org/10.1038/s43587-024-00695-z (2024).
Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).
Duran, I. et al. Detection of senescence using machine learning algorithms based on nuclear features. Nat. Commun. 15, 1041 (2024).
McHugh, D. et al. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells. Nat. Cell Biol. 25, 1804–1820 (2023).
Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
Gu, L. et al. FBP1 controls liver cancer evolution from senescent MASH hepatocytes. Nature 637, 461–469 (2025). This study identified that FPB1 is a critical break preventing the transition of senescent MASH hepatocytes towards carcinogenesis.
Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).
Grohmann, M. et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306 (2018). This study showed that MASH and fibrosis can be uncoupled from HCC development in a STAT-dependent manner.
Kazankov, K. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16, 145–159 (2019).
Zhang, T., Horn, P., Peiseler, M. & Tacke, F. Macrophage heterogeneity and plasticity in liver injury and repair mechanisms. Stem Cells https://doi.org/10.1093/stmcls/sxaf072 (2025).
Miyamoto, Y. et al. Periportal macrophages protect against commensal-driven liver inflammation. Nature 629, 901–909 (2024).
Cai, B. et al. Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab. 31, 406–421 (2020).
Govaere, O. et al. Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease. J. Hepatol. 76, 1001–1012 (2022).
Tran, S. et al. Impaired Kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis. Immunity 53, 627–640 (2020). This study showed that lipotoxicity during MASLD progression impairs Kupffer cell renewal, resulting in monocyte-derived Kupffer cells that contribute to the Kupffer cell pool.
Miura, K., Yang, L., van Rooijen, N., Ohnishi, H. & Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310–G1321 (2012).
Pradere, J. P. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461–1473 (2013).
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010). This study showed that obesity promote hepatic inflammation and tumorigenesis through IL-6 and TNF.
Boesch, M. et al. Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis. Nat. Genetics https://doi.org/10.1038/s41588-026-02600-3 (2026).
Han, H. et al. Macrophage-derived osteopontin (SPP1) protects from nonalcoholic steatohepatitis. Gastroenterology 165, 201–217 (2023).
Remmerie, A. et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, 641–657 (2020).
Li, Z. et al. Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease. Nat. Genet. 57, 3112–3125 (2025).
Hendrikx, T. et al. Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH. J. Hepatol. 77, 1373–1385 (2022).
Wang, X. et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity 56, 58–77 (2023).
Ganguly, S. et al. Lipid-associated macrophages’ promotion of fibrosis resolution during MASH regression requires TREM2. Proc. Natl Acad. Sci. USA 121, e2405746121 (2024).
De Ponti, F. F. et al. Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair. Immunity 58, 362–380 (2025).
Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).
Zhou, L. et al. Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation. Sci. Transl. Med. 16, eadk1866 (2024).
Guillot, A. et al. Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression. Hepatology 78, 150–166 (2023).
Liu, H. et al. Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming. Gut https://doi.org/10.1136/gutjnl-2024-334425 (2025).
Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).
Brunt, E. M. et al. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 49, 809–820 (2009).
Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021). This study showed that MASH-HCC is less efficacious to immunotherapy in preclinical mouse models.
Dudek, M. et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592, 444–449 (2021). The authors showed that tissue-resident CXCR6+CD8+ T cells display an autoaggressive phenotype that promotes MASH.
Krenkel, O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 67, 1270–1283 (2018).
Kotsiliti, E. et al. Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling. J. Hepatol. 79, 296–313 (2023).
Ramadori, P., Klag, T., Malek, N. P. & Heikenwalder, M. Platelets in chronic liver disease, from bench to bedside. JHEP Rep. 1, 448–459 (2019).
Deczkowska, A. et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat. Med. 27, 1043–1054 (2021).
Petriv, N. et al. Essential roles of B cell subsets in the progression of MASLD and HCC. JHEP Rep. https://doi.org/10.1016/j.jhepr.2024.101189 (2024).
Li, L. et al. MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance. Exp. Cell. Res. 407, 112801 (2021).
Sanyal, A. J. et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N. Engl. J. Med. 385, 1559–1569 (2021).
Lin, H. et al. Vibration-controlled transient elastography scores to predict liver-related events in steatotic liver disease. JAMA 331, 1287–1297 (2024).
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J. Hepatol. 81, 492–542 (2024). The European guidelines for the clinical management of MASLD.
Paternostro, R. et al. Hepatic venous pressure gradient predicts risk of hepatic decompensation and liver-related mortality in patients with MASLD. J. Hepatol. https://doi.org/10.1016/j.jhep.2024.05.033 (2024).
Hammerich, L. & Tacke, F. Hepatic inflammatory responses in liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 20, 633–646 (2023).
Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology 158, 1913–1928 (2020).
Lei, L. et al. Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis. Hepatology 76, 1360–1375 (2022).
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
Kim, H. Y. et al. Multi-modal analysis of human hepatic stellate cells identifies novel therapeutic targets for metabolic dysfunction-associated steatotic liver disease. J. Hepatol. https://doi.org/10.1016/j.jhep.2024.10.044 (2024).
Sugimoto, A. et al. Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. Nature 640, 752–761 (2025).
Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356–365 (2022).
Trinh, V. Q. et al. Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation. Sci. Signal. 16, eadf6696 (2023).
Bogomolova, A., Balakrishnan, A., Ott, M. & Sharma, A. D. “The Good, the Bad, and the Ugly”—about diverse phenotypes of hepatic stellate cells in the liver. Cell. Mol. Gastroenterol. Hepatol. 17, 607–622 (2024).
Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).
Horn, P. & Tacke, F. Metabolic reprogramming in liver fibrosis. Cell Metab. 36, 1439–1455 (2024).
Bendixen, S. M. et al. Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module. J. Hepatol. 80, 467–481 (2024).
Wang, S. et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 15, eadd3949 (2023).
Yashaswini, C. N. et al. Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis. J. Hepatol. 81, 207–217 (2024).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).
Yashaswini, C. N. et al. Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction–associated steatohepatitis. Sci. Transl. Med. 18, eadx0368 (2026).
Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020).
Dai, H. et al. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J. Hepatol. 80, 913–927 (2024).
Peiseler, M. et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease—novel insights into cellular communication circuits. J. Hepatol. 77, 1136–1160 (2022).
Lau, H. C., Zhang, X. & Yu, J. Gut microbiome in metabolic dysfunction-associated steatotic liver disease and associated hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-025-01089-1 (2025).
Lang, S. et al. Intestinal virome signature associated with severity of nonalcoholic fatty liver disease. Gastroenterology 159, 1839–1852 (2020).
Demir, M. et al. The fecal mycobiome in non-alcoholic fatty liver disease. J. Hepatol. 76, 788–799 (2022).
Mouries, J. et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J. Hepatol. 71, 1216–1228 (2019).
Llorente, C. et al. mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity. Nature 646, 180–189 (2025). This study showed that intestinal antimicrobial immunity reduces bacterial translocation to protect against MASH.
Zhang, P. et al. IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis. Cell Metab. 36, 2341–2354 (2024).
Harte, A. L. et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J. Inflamm. 7, 15 (2010).
Carpino, G. et al. Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology 72, 470–485 (2020).
Ferslew, B. C. et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig. Dis. Sci. 60, 3318–3328 (2015).
Jiao, N. et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut 67, 1881–1891 (2018).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). This study showed that the obesity-induced secondary bile acid DCA drives liver injury and liver cancer.
Aranha, M. M. et al. Bile acid levels are increased in the liver of patients with steatohepatitis. Eur. J. Gastroenterol. Hepatol. 20, 519–525 (2008).
Zhang, X. et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut 70, 761–774 (2021).
Gallage, S. et al. Spontaneous cholemia in C57BL/6 mice predisposes to liver cancer in NASH. Cell. Mol. Gastroenterol. Hepatol. 13, 875–878 (2022).
Fuchs, C. D. & Trauner, M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat. Rev. Gastroenterol. Hepatol. 19, 432–450 (2022).
Sun, L., Cai, J. & Gonzalez, F. J. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 18, 335–347 (2021).
Beraza, N. et al. Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut 60, 387–396 (2011).
Yang, M. et al. Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nat. Commun. 14, 228 (2023).
Loo, T. M. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017).
Meijnikman, A. S. et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nat. Med. 28, 2100–2106 (2022).
Yuan, J. et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 30, 675–688 (2019).
Song, Q. et al. Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma. J. Hepatol. 79, 1352–1365 (2023).
Nie, Q. et al. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway. Cell 187, 2717–2734 (2024).
Gallage, S. et al. A researcher’s guide to preclinical mouse NASH models. Nat. Metab. 4, 1632–1649 (2022).
Leslie, J. et al. Metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-025-01162-9 (2026).
Karasawa, T. et al. Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice. Cell Metab. 37, 1619–1620 (2025).
Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat. Med. 31, 951–962 (2025).
West, S. et al. Weight regain after cessation of medication for weight management: systematic review and meta-analysis. Brit. Med. J. 392, e085304 (2026).
Albhaisi, S., Chowdhury, A. & Sanyal, A. J. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 1, 329–341 (2019).
Sato-Espinoza, K., Chotiprasidhi, P., Huaman, M. R. & Díaz-Ferrer, J. Update in lean metabolic dysfunction-associated steatotic liver disease. World J. Hepatol. 16, 452–464 (2024).
Danpanichkul, P., Suparan, K., Kim, D. & Wijarnpreecha, K. What is new in metabolic dysfunction-associated steatotic liver disease in lean individuals: from bench to bedside. J. Clin. Med. https://doi.org/10.3390/jcm13010278 (2024).
Eslam, M. et al. Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nat. Rev. Gastroenterol. Hepatol. 19, 638–651 (2022).
Hagström, H. et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study. Hepatol. Commun. 2, 48–57 (2018).
Huo, Z. et al. Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts. Gut https://doi.org/10.1136/gutjnl-2025-336127 (2025).
Ezeani, C., Omaliko, C., Al-Ajlouni, Y. A. & Njei, B. Mortality, hepatic decompensation, and cardiovascular- and renal-related outcomes in lean versus non-lean patients hospitalized with metabolic dysfunction-associated steatohepatitis (MASH). Cureus 16, e60968 (2024).
Petersen, K. F., Dufour, S., Li, F., Rothman, D. L. & Shulman, G. I. Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals. JCI Insight https://doi.org/10.1172/jci.insight.157906 (2022).
Tuomola, N. et al. Mildly elevated liver lipid content is characterised by reduced insulin sensitivity. JHEP Rep. https://doi.org/10.1016/j.jhepr.2025.101535 (2025).
Chen, F. et al. Lean NAFLD: a distinct entity shaped by differential metabolic adaptation. Hepatology 71, 1213–1227 (2020). This study showed that MASLD in lean individuals display a distinct bile acid and microbial profile as well as a metabolic profile.
Alharthi, J. et al. Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming. Metabolism 144, 155583 (2023).
