Younossi, Z. M., Kalligeros, M. & Henry, L. Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clin. Mol. Hepatol. 31, S32–S50 (2025).
Article PubMed Google Scholar
Graupera, I. et al. Prevalence of liver fibrosis in the general population (the LiverScreen project): a multinational European cohort study. Lancet 407, 1448–1458 (2026). This prospective study provides data on the prevalence and risk factors for liver fibrosis in the general population in Europe.
Article PubMed Google Scholar
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).
Article PubMed Google Scholar
Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023). This multisociety international consensus paper establishes the current terminology of MASLD and MASH, replacing former definitions of NAFLD, NASH or MAFLD.
Article CAS PubMed Google Scholar
Llovet, J. M. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat. Rev. Gastroenterol. Hepatol. 20, 487–503 (2023).
Article CAS PubMed PubMed Central Google Scholar
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).
Article CAS PubMed Google Scholar
Targher, G., Byrne, C. D. & Tilg, H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 73, 691–702 (2024).
Article CAS PubMed Google Scholar
Brunt, E. M. et al. Complexity of ballooned hepatocyte feature recognition: defining a training atlas for artificial intelligence-based imaging in NAFLD. J. Hepatol. 76, 1030–1041 (2022).
Article CAS PubMed PubMed Central Google Scholar
Ratziu, V. et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128, 1898–1906 (2005).
Article PubMed Google Scholar
Bedossa, P. et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 56, 1751–1759 (2012).
Article PubMed Google Scholar
Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).
Article PubMed Google Scholar
Naoumov, N. V. et al. Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH. J. Hepatol. 77, 1399–1409 (2022).
Article CAS PubMed Google Scholar
Ratziu, V. et al. Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: current status and future directions. J. Hepatol. 80, 335–351 (2024).
Article CAS PubMed Google Scholar
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. https://doi.org/10.1016/j.jhep.2024.04.031 (2024). This multidisciplinary international guideline provides evidence-based recommendations on case finding, diagnosis, risk stratification and treatment of MASLD.
Anstee, Q. M. et al. Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study. Lancet Reg. Health Eur. 36, 100780 (2024).
Article PubMed Google Scholar
Loosen, S. H. et al. An elevated FIB-4 score predicts liver cancer development: a longitudinal analysis from 29,999 patients with NAFLD. J. Hepatol. 76, 247–248 (2022).
Article CAS PubMed Google Scholar
Mózes, F. E. et al. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis. Lancet Gastroenterol. Hepatol. 8, 704–713 (2023).
Article PubMed Google Scholar
Vali, Y. et al. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study. Lancet Gastroenterol. Hepatol. 8, 714–725 (2023).
Article CAS PubMed Google Scholar
Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330–344 (2013).
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N. Engl. J. Med. 392, 2089–2099 (2025). This phase III trial demonstrates histological improvement of MASH and fibrosis with weekly 2.4 mg semaglutide over 72 weeks, leading to accelerated approval in this indication.
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N. Engl. J. Med. 391, 311–319 (2024).
Article CAS PubMed Google Scholar
Loomba, R. et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med. 391, 299–310 (2024).
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).
Article CAS PubMed PubMed Central Google Scholar
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). This phase III trial provides evidence that resmetirom improves MASH resolution and fibrosis improvement in MASH after 52 weeks, leading to accelerated approval in this indication.
Article PubMed Google Scholar
Verrastro, O. et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet 401, 1786–1797 (2023). This prospective trial demonstrates the efficacy of bariatric surgery on liver histology for individuals with early-stage MASH.
Article PubMed Google Scholar
Liu, H., Lefere, S., Guillot, A., Zheng, M. H. & Tacke, F. Bariatric surgery for metabolic dysfunction-associated steatotic liver disease (MASLD): current knowledge of mechanisms. Hepatology https://doi.org/10.1097/hep.0000000000001417 (2025).
Article PubMed PubMed Central Google Scholar
Aminian, A. et al. Long-term liver outcomes after metabolic surgery in compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis. Nat. Med. 31, 988–995 (2025).
Article MathSciNet CAS PubMed Google Scholar
Gallage, S. et al. Molecular mechanisms and pathogenesis of MASH. Nature (in the press).
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).
Article CAS PubMed PubMed Central Google Scholar
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).
Article CAS PubMed Google Scholar
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).
Article CAS PubMed PubMed Central Google Scholar
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
Article CAS PubMed PubMed Central Google Scholar
Raverdy, V. et al. Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease. Nat. Med. 30, 3624–3633 (2024).
Article CAS PubMed PubMed Central Google Scholar
Jamialahmadi, O. et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease. Nat. Med. 30, 3614–3623 (2024).
Article CAS PubMed PubMed Central Google Scholar
Ding, J. et al. Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Sci. Transl. Med. 16, eadh9940 (2024).
Article CAS PubMed Google Scholar
Cherubini, A. et al. Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nat. Med. 29, 2643–2655 (2023).
Article CAS PubMed PubMed Central Google Scholar
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).
Article CAS PubMed Google Scholar
Chen, V. L. et al. Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort. J. Hepatol. 81, 379–388 (2024).
Article CAS PubMed PubMed Central Google Scholar
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).
Article PubMed Google Scholar
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).
Article CAS PubMed Google Scholar
Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).
Article CAS PubMed Google Scholar
Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).
Article CAS PubMed PubMed Central Google Scholar
Donati, B. et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci. Rep. 7, 4492 (2017).
Article PubMed PubMed Central Google Scholar
Teo, K. et al. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: a meta-analysis. J. Hepatol. 74, 20–30 (2021).
Article CAS PubMed Google Scholar
Du, M. et al. Cross-trait genomic modeling reveals the polygenic architecture and systemic impact of MASLD. Sci. Adv. 12, eaeb5665 (2026).
Article CAS PubMed PubMed Central Google Scholar
Liu, Z. et al. Population stratification using MASLD polygenic risk score improves severe liver disease prediction by clinical fibrosis scores. Dig. Liver Dis. 57, 1819–1825 (2025).
Article CAS PubMed Google Scholar
Vilar-Gomez, E. et al. Genetic and non-genetic drivers of histological progression and regression in MASLD. J. Hepatol. 84, 502–516 (2026).
Article CAS PubMed Google Scholar
Puengel, T. & Tacke, F. Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today? Expert Opin. Pharmacother. 25, 1249–1263 (2024).
Article CAS PubMed Google Scholar
Krag, A., Tacke, F., Israelsen, M. & Younossi, Z. M. Is liver steatosis a disease or the emperor’s new clothes? J. Hepatol. 84, 993–1001 (2026).
Article PubMed Google Scholar
Cheung, A. et al. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the Liver Forum. Hepatology 70, 1841–1855 (2019).
Article PubMed Google Scholar
Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54, 344–353 (2011).
Article PubMed PubMed Central Google Scholar
Anania, F. A. et al. Non-invasive tests: establishing efficacy for metabolic dysfunction-associated steatohepatitis beyond the biopsy—current perspectives from the Division of Hepatology and Nutrition, US Food and Drug Administration. Hepatology https://doi.org/10.1097/hep.0000000000001509 (2025).
Article PubMed Google Scholar
Loomba, R., Ratziu, V. & Harrison, S. A. Expert panel review to compare FDA and EMA guidance on drug development and endpoints in nonalcoholic steatohepatitis. Gastroenterology 162, 680–688 (2022).
Article CAS PubMed Google Scholar
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).
Article CAS PubMed PubMed Central Google Scholar
US Food and Drug Administration. FDA approves first treatment for patients with liver scarring due to fatty liver disease. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease (2024).
Rezdiffra. EMA https://www.ema.europa.eu/en/medicines/human/EPAR/rezdiffra (2025).
US Food and Drug Administration. FDA approves treatment for serious liver disease known as ‘MASH’. FDA https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash (2025).
Chen, V. L. et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD practice guidance. Hepatology 81, 312–320 (2025).
Article PubMed Google Scholar
Aminian, A. et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA 326, 2031–2042 (2021).
Article PubMed PubMed Central Google Scholar
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).
Article CAS PubMed PubMed Central Google Scholar
Taylor, R. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab. 28, 547–556.e3 (2018).
Article CAS PubMed Google Scholar
Vilar-Gomez, E. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 367–378.e5 (2015). This prospective trial confirms the efficacy of rigorous lifestyle management in patients with MASH, showing that 10% weight loss over 1 year associates with liver fibrosis regression.
Article PubMed Google Scholar
Clifton, K. K., Ma, C. X., Fontana, L. & Peterson, L. L. Intermittent fasting in the prevention and treatment of cancer. CA Cancer J. Clin. 71, 527–546 (2021).
PubMed Google Scholar
Minciuna, I., Gallage, S., Heikenwalder, M., Zelber-Sagi, S. & Dufour, J. F. Intermittent fasting—the future treatment in NASH patients? Hepatology 78, 1290–1305 (2023).
Article PubMed Google Scholar
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.e7 (2024).
Article CAS PubMed Google Scholar
Holmer, M. et al. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet—a randomised controlled trial. JHEP Rep. 3, 100256 (2021).
Article PubMed PubMed Central Google Scholar
Wang, Y. Y., Tian, F., Qian, X. L., Ying, H. M. & Zhou, Z. F. Effect of 5:2 intermittent fasting diet versus daily calorie restriction eating on metabolic-associated fatty liver disease—a randomized controlled trial. Front. Nutr. 11, 1439473 (2024).
Article PubMed PubMed Central Google Scholar
Wilkinson, M. J. et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 31, 92–104.e5 (2020).
Article CAS PubMed Google Scholar
Feehan, J. et al. Time-restricted fasting improves liver steatosis in non-alcoholic fatty liver disease—a single blinded crossover trial. Nutrients 15, 4870 (2023).
Article CAS PubMed PubMed Central Google Scholar
Kord-Varkaneh, H., Salehi-Sahlabadi, A., Tinsley, G. M., Santos, H. O. & Hekmatdoost, A. Effects of time-restricted feeding (16/8) combined with a low-sugar diet on the management of non-alcoholic fatty liver disease: a randomized controlled trial. Nutrition 105, 111847 (2023).
Article CAS PubMed Google Scholar
Oh, J. H. et al. Efficacy and safety of time-restricted eating in metabolic dysfunction-associated steatotic liver disease. J. Hepatol. 83, 1256–1265 (2025).
Article CAS PubMed Google Scholar
Wei, X. et al. Effects of time-restricted eating on nonalcoholic fatty liver disease: the TREATY-FLD randomized clinical trial. JAMA Netw. Open 6, e233513 (2023).
Article PubMed PubMed Central Google Scholar
Scragg, J. et al. Feasibility of a very low calorie diet to achieve a sustainable 10% weight loss in patients with nonalcoholic fatty liver disease. Clin. Transl. Gastroenterol. 11, e00231 (2020).
Article PubMed PubMed Central Google Scholar
Houghton, D. et al. Exercise reduces liver lipids and visceral adiposity in patients with nonalcoholic steatohepatitis in a randomized controlled trial. Clin. Gastroenterol. Hepatol. 15, 96–102.e3 (2017).
Article CAS PubMed Google Scholar
Mucinski, J. M. et al. Histological improvements following energy restriction and exercise: the role of insulin resistance in resolution of MASH. J. Hepatol. 81, 781–793 (2024).
Article CAS PubMed PubMed Central Google Scholar
Ezpeleta, M. et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab. 35, 56–70.e3 (2023).
Article CAS PubMed Google Scholar
Lassailly, G. et al. Resolution of metabolic dysfunction-associated steatohepatitis with no worsening of fibrosis after bariatric surgery improves 15-year survival: a prospective cohort study. Clin. Gastroenterol. Hepatol. 23, 1567–1576.e9 (2025).
Article CAS PubMed Google Scholar
Patton, H., Heimbach, J. & McCullough, A. AGA clinical practice update on bariatric surgery in cirrhosis: expert review. Clin. Gastroenterol. Hepatol. 19, 436–445 (2021).
Article PubMed Google Scholar
Temime, V. et al. Outcomes of bariatric surgery in the setting of compensated advanced chronic liver disease associated with clinically significant portal hypertension: a multicenter, retrospective, cohort study on feasibility and safety. Int. J. Surg. 110, 3562–3570 (2024).
Article PubMed PubMed Central Google Scholar
Larson, E. L. et al. Simultaneous liver transplant and sleeve gastrectomy provides durable weight loss, improves metabolic syndrome and reduces allograft steatosis. J. Hepatol. 83, 729–737 (2025).
Article CAS PubMed Google Scholar
Pais, R. et al. Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Hepatology 76, 456–468 (2022).
Article CAS PubMed Google Scholar
Tacke, F., Puengel, T., Loomba, R. & Friedman, S. L. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J. Hepatol. 79, 552–566 (2023).
Article CAS PubMed PubMed Central Google Scholar
Wirth, E. K., Puengel, T., Spranger, J. & Tacke, F. Thyroid hormones as a disease modifier and therapeutic target in nonalcoholic steatohepatitis. Expert Rev. Endocrinol. Metab. 17, 425–434 (2022).
Article CAS PubMed Google Scholar
Kelly, M. J. et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a highly selective thyroid hormone receptor β agonist in clinical trials for the treatment of dyslipidemia. J. Med. Chem. 57, 3912–3923 (2014).
Article CAS PubMed Google Scholar
Taub, R. et al. Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist. Atherosclerosis 230, 373–380 (2013).
Article CAS PubMed Google Scholar
Dubois, V., Lefebvre, P., Staels, B. & Eeckhoute, J. Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease. Gut 73, 1562–1569 (2024).
Article CAS PubMed Google Scholar
Staels, B., Butruille, L. & Francque, S. Treating NASH by targeting peroxisome proliferator-activated receptors. J. Hepatol. 79, 1302–1316 (2023).
Article CAS PubMed Google Scholar
Lefere, S. et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 73, 757–770 (2020).
Article CAS PubMed Google Scholar
Francque, S. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat. Rev. Gastroenterol. Hepatol. 18, 24–39 (2021).
Article PubMed Google Scholar
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).
Article CAS PubMed Google Scholar
Adorini, L. & Trauner, M. FXR agonists in NASH treatment. J. Hepatol. 79, 1317–1331 (2023).
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J. Hepatol. 79, 1110–1120 (2023).
Article CAS PubMed Google Scholar
Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019). This phase III trial provides a positive interim analysis for histological end points in MASH, but obeticholic acid ultimately did not reach criteria for regulatory approval.
Article CAS PubMed Google Scholar
Goetz, R. et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417–3428 (2007).
Article CAS PubMed PubMed Central Google Scholar
Ogawa, Y. et al. βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432–7437 (2007).
Article CAS PubMed PubMed Central Google Scholar
Ornitz, D. M. & Itoh, N. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4, 215–266 (2015).
Article CAS PubMed PubMed Central Google Scholar
Kharitonenkov, A. et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J. Cell. Physiol. 215, 1–7 (2008).
Article CAS PubMed Google Scholar
Kurosu, H. et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).
Article CAS PubMed PubMed Central Google Scholar
Yie, J. et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett. 583, 19–24 (2009).
Article CAS PubMed Google Scholar
Lee, J. H. et al. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am. J. Transl. Res. 8, 4750–4763 (2016).
CAS PubMed PubMed Central Google Scholar
Tanaka, N. et al. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim. Biophys. Acta 1852, 1242–1252 (2015).
Article CAS PubMed PubMed Central Google Scholar
Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009).
Article CAS PubMed Google Scholar
Singhal, G. et al. Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol. Metab. 13, 56–66 (2018).
Article CAS PubMed PubMed Central Google Scholar
Le, C. T., Nguyen, G., Park, S. Y., Choi, D. H. & Cho, E. H. LY2405319, an analog of fibroblast growth factor 21 ameliorates α-smooth muscle actin production through inhibition of the succinate-G-protein couple receptor 91 (GPR91) pathway in mice. PLoS ONE 13, e0192146 (2018).
Article PubMed PubMed Central Google Scholar
Yu, Y. et al. Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway. Int. Immunopharmacol. 38, 144–152 (2016).
Article CAS PubMed Google Scholar
Harrison, S. A., Rolph, T., Knott, M. & Dubourg, J. FGF21 agonists: an emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond. J. Hepatol. 81, 562–576 (2024).
Article CAS PubMed Google Scholar
Loomba, R. et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study. Clin. Gastroenterol. Hepatol. 22, 102–112.e9 (2024).
Article CAS PubMed Google Scholar
Harrison, S. A. et al. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 8, 1080–1093 (2023).
Article CAS PubMed Google Scholar
Noureddin, M. et al. Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet 406, 719–730 (2025).
Article CAS PubMed Google Scholar
Noureddin, M. et al. Efruxifermin in compensated liver cirrhosis caused by MASH. N. Engl. J. Med. 392, 2413–2424 (2025). This phase IIb trial demonstrates a fibrosis regression in MASH–cirrhosis, using the FGF21 analogue efruxifermin for 96 weeks.
Article CAS PubMed Google Scholar
Noureddin, M. et al. Efimosfermin alfa (BOS-580) once per month in people with metabolic dysfunction-associated steatohepatitis with F2 or F3 fibrosis: results from a 24-week, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 407, 794–804 (2026).
Article CAS PubMed Google Scholar
Loomba, R. et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N. Engl. J. Med. 389, 998–1008 (2023).
Article CAS PubMed PubMed Central Google Scholar
Esler, W. P. & Cohen, D. E. Pharmacologic inhibition of lipogenesis for the treatment of NAFLD. J. Hepatol. 80, 362–377 (2024).
Article CAS PubMed Google Scholar
Ratziu, V. et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat. Med. 27, 1825–1835 (2021).
Article CAS PubMed PubMed Central Google Scholar
Loomba, R. et al. Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 406, 821–831 (2025).
Article CAS PubMed Google Scholar
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. 10, 924–940 (2025).
Article CAS PubMed Google Scholar
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).
Article PubMed PubMed Central Google Scholar
Mantovani, A., Byrne, C. D. & Targher, G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. Lancet Gastroenterol. Hepatol. 7, 367–378 (2022).
Article CAS PubMed Google Scholar
Lin, J. et al. Effect of dapagliflozin on metabolic dysfunction-associated steatohepatitis: multicentre, double blind, randomised, placebo controlled trial. BMJ 389, e083735 (2025).
Article CAS PubMed PubMed Central Google Scholar
Lindén, D. & Romeo, S. Therapeutic opportunities for the treatment of NASH with genetically validated targets. J. Hepatol. 79, 1056–1064 (2023).
Article PubMed Google Scholar
Armisen, J. et al. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomized phase I trials. J. Hepatol. 83, 31–42 (2025).
Article CAS PubMed Google Scholar
Newsome, P. N. & Ambery, P. Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver. J. Hepatol. 79, 1557–1565 (2023).
Article CAS PubMed Google Scholar
Wong, C. K. & Drucker, D. J. Antiinflammatory actions of glucagon-like peptide-1-based therapies beyond metabolic benefits. J. Clin. Invest. 135, e194751 (2025).
Article CAS PubMed PubMed Central Google Scholar
Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).
Article CAS PubMed Google Scholar
Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).
Article CAS PubMed Google Scholar
Loomba, R. et al. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 8, 511–522 (2023).
Article CAS PubMed PubMed Central Google Scholar
Meyhöfer, S. M. et al. Semaglutide on liver fibrosis and heart outcomes in patients at high risk of liver fibrosis: a prespecified analysis of the SELECT randomized trial. Nat. Med. 32, 1686–1693 (2026). This prespecified analysis of a large prospective trial using 2.4 mg semaglutide indicates benefits for cardiovascular outcomes in individuals with presumed MASLD or MASH.
Article PubMed PubMed Central Google Scholar
Deanfield, J. et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet 406, 2257–2268 (2025).
Article CAS PubMed Google Scholar
Gonzalez-Rellan, M. J. et al. The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors. Cell Metab. https://doi.org/10.1016/j.cmet.2026.03.011 (2026).
Article PubMed Google Scholar
Shankar, S. S. et al. Safety and efficacy of novel incretin co-agonist cotadutide in biopsy-proven noncirrhotic MASH with fibrosis. Clin. Gastroenterol. Hepatol. 22, 1847–1857.e11 (2024).
Article CAS PubMed Google Scholar
Romero-Gómez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).
Article PubMed Google Scholar
Harrison, S. A. et al. Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: a randomized, double-blind, placebo-controlled study. J. Hepatol. https://doi.org/10.1016/j.jhep.2024.07.006 (2024).
Article PubMed Google Scholar
Noureddin, M. et al. Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 24-week results from a multicentre, randomised, double-blind, phase 2b study. Lancet 406, 2644–2655 (2025).
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat. Med. 30, 2037–2048 (2024).
Article CAS PubMed PubMed Central Google Scholar
Jara, M. et al. Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis. Nat. Med. 31, 3128–3140 (2025).
Article CAS PubMed PubMed Central Google Scholar
Bansal, M. B. et al. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD practice guidance. Hepatology https://doi.org/10.1097/hep.0000000000001608 (2025).
Article PubMed Google Scholar
Guillot, A. & Tacke, F. Liver macrophages revisited: the expanding universe of versatile responses in a spatiotemporal context. Hepatol. Commun. 8, e0491 (2024).
Article PubMed PubMed Central Google Scholar
Ratziu, V. et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology 72, 892–905 (2020).
Article CAS PubMed Google Scholar
Anstee, Q. M. et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA phase III randomized study. Clin. Gastroenterol. Hepatol. 22, 124–134.e1 (2024).
Article CAS PubMed Google Scholar
Schwabe, R. F., Tacke, F., Sugimoto, A. & Friedman, S. L. Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease. JHEP Rep. 7, 101421 (2025).
Article PubMed PubMed Central Google Scholar
Harrison, S. A. et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J. Hepatol. 73, 26–39 (2020).
Article CAS PubMed Google Scholar
Dwyer, B. J., Macmillan, M. T., Brennan, P. N. & Forbes, S. J. Cell therapy for advanced liver diseases: repair or rebuild. J. Hepatol. 74, 185–199 (2021).
Article CAS PubMed Google Scholar
Brennan, P. N. et al. Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomized controlled trial. Nat. Med. 31, 979–987 (2025).
Article CAS PubMed PubMed Central Google Scholar
Moroni, F. et al. Safety profile of autologous macrophage therapy for liver cirrhosis. Nat. Med. 25, 1560–1565 (2019).
Article CAS PubMed Google Scholar
Dai, H. et al. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J. Hepatol. 80, 913–927 (2024).
Article CAS PubMed Google Scholar
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).
Article CAS PubMed PubMed Central Google Scholar
Ramadori, P., Klag, T., Malek, N. P. & Heikenwalder, M. Platelets in chronic liver disease, from bench to bedside. JHEP Rep. 1, 448–459 (2019).
Article PubMed PubMed Central Google Scholar
Baratta, F. et al. Platelet thromboxane B2 overproduction associated with liver fibrosis severity in patients with MASLD. Thromb. Res. 257, 109540 (2025).
Article PubMed Google Scholar
Horn, P. & Tacke, F. Metabolic reprogramming in liver fibrosis. Cell Metab. 36, 1439–1455 (2024).
Article CAS PubMed Google Scholar
Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020).
Article CAS PubMed PubMed Central Google Scholar
Yashaswini, C. N. et al. Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis. J. Hepatol. 81, 207–217 (2024).
Article CAS PubMed PubMed Central Google Scholar
Illert, A. L. et al. The German Network for Personalized Medicine to enhance patient care and translational research. Nat. Med. 29, 1298–1301 (2023).
Article CAS PubMed Google Scholar
Loomba, R. et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology 73, 625–643 (2021).
Article CAS PubMed Google Scholar
Loomba, R. et al. Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 9, 1090–1100 (2024).
Article CAS PubMed Google Scholar
Harrison, S. A. et al. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 7, 603–616 (2022).
Article CAS PubMed Google Scholar
Harrison, S. A. et al. A phase IIb randomised-controlled trial of the FFAR1/FFAR4 agonist icosabutate in MASH. J. Hepatol. 83, 293–303 (2025).
Article CAS PubMed Google Scholar
Harrison, S. A. et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther. 59, 51–63 (2024).
Article CAS PubMed Google Scholar
Lian, B. Results from the 52-week phase 2b VOYAGE trial of VK2809 in patients with biopsy-confirmed non-alcoholic steatohepatitis and fibrosis: a randomized, placebo-controlled trial [The Liver Meeting: San Diego, 2024; Late Breaker #5016]. Hepatology 80, S1–S2011 (2024).
Google Scholar
Noureddin, M. et al. TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial. Nat. Med. 31, 2297–2305 (2025).
Article PubMed PubMed Central Google Scholar
Harrison, S. A. et al. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: a phase II randomized placebo-controlled trial (DESTINY-1). J. Hepatol. 78, 914–925 (2023).
Article CAS PubMed Google Scholar
Siddiqui, M. S. et al. A phase 2 double blinded, randomized controlled trial of saroglitazar in patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 19, 2670–2672 (2021).
Article PubMed Google Scholar
Harrison, S. A. et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J. Hepatol. 72, 816–827 (2020).
Article CAS PubMed Google Scholar
Harrison, S. A. et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 155, 1140–1153 (2018).
Article CAS PubMed Google Scholar
Lazarus, J. V. et al. The global NAFLD policy review and preparedness index: are countries ready to address this silent public health challenge? J. Hepatol. 76, 771–780 (2022).
Article CAS PubMed Google Scholar
Davison, B. A. et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials. J. Hepatol. 73, 1322–1332 (2020).
Article CAS PubMed Google Scholar
Zoncapè, M., Liguori, A. & Tsochatzis, E. A. Non-invasive testing and risk-stratification in patients with MASLD. Eur. J. Intern. Med. 122, 11–19 (2024).
Article PubMed Google Scholar
Anstee, Q. M., Castera, L. & Loomba, R. Impact of non-invasive biomarkers on hepatology practice: past, present and future. J. Hepatol. 76, 1362–1378 (2022).
Article CAS PubMed Google Scholar
Taylor, R. S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 158, 1611–1625.e12 (2020).
Article CAS PubMed Google Scholar
Sterling, R. K. et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 43, 1317–1325 (2006).
Article CAS PubMed Google Scholar
Boyle, M. et al. Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic fatty liver disease. JHEP Rep. 1, 188–198 (2019).
Article PubMed PubMed Central Google Scholar
Mak, A. L. et al. Systematic review with meta-analysis: diagnostic accuracy of PRO-C3 for hepatic fibrosis in patients with non-alcoholic fatty liver disease. Biomedicines 9, 1920 (2021).
Article CAS PubMed PubMed Central Google Scholar
Rosenberg, W. M. et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 127, 1704–1713 (2004).
Article PubMed Google Scholar
Daniels, S. J. et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 69, 1075–1086 (2019).
Article CAS PubMed Google Scholar
Mózes, F. E. et al. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut 71, 1006–1019 (2022).
Article PubMed Google Scholar
Pavlides, M. et al. Prospective validation of imaging and serum diagnostic biomarkers of steatohepatitis and fibrosis in MASLD: the LITMUS Imaging Study. Nat. Med. https://doi.org/10.1038/s41591-026-04496-2 (2026).
Article PubMed PubMed Central Google Scholar
Vali, Y. et al. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-analysis. J. Hepatol. 73, 252–262 (2020).
Article PubMed Google Scholar
Vali, Y. et al. FibroTest for evaluating fibrosis in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis. J. Clin. Med. 10, 2415 (2021).
Article PubMed PubMed Central Google Scholar
Van Dijk, A. M. et al. Systematic review with meta-analyses: diagnostic accuracy of FibroMeter tests in patients with non-alcoholic fatty liver disease. J. Clin. Med. 10, 2910 (2021).
Article PubMed PubMed Central Google Scholar
Sanyal, A. J. et al. Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis. Nat. Med. 29, 2656–2664 (2023).
Article CAS PubMed PubMed Central Google Scholar
Rinella, M. E. et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77, 1797–1835 (2023).
Article PubMed PubMed Central Google Scholar
Fichez, J. et al. Non-invasive tests for fibrotic MASH for reducing screen failure in therapeutic trials. JHEP Rep. 7, 101351 (2025).
Article PubMed PubMed Central Google Scholar
Yip, T. C. et al. Prognostic performance of the two-step clinical care pathway in metabolic dysfunction-associated steatotic liver disease. J. Hepatol. 83, 304–314 (2025).
Article CAS PubMed Google Scholar
Govaere, O. et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Sci. Transl. Med. 12, eaba4448 (2020).
Article CAS PubMed Google Scholar
Kozumi, K. et al. Transcriptomics identify thrombospondin-2 as a biomarker for NASH and advanced liver fibrosis. Hepatology 74, 2452–2466 (2021).
Article CAS PubMed PubMed Central Google Scholar
Hoang, S. A. et al. Gene expression predicts histological severity and reveals distinct molecular profiles of nonalcoholic fatty liver disease. Sci. Rep. 9, 12541 (2019).
Article PubMed PubMed Central Google Scholar
Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).
Article CAS PubMed PubMed Central Google Scholar
Corey, K. E. et al. ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. J. Hepatol. 76, 25–33 (2022).
Article CAS PubMed Google Scholar
Sanyal, A. J. et al. Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 78, 693–703 (2023).
Article CAS PubMed Google Scholar
Indira Chandran, V. et al. Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness. Hepatology 77, 558–572 (2023).
Article PubMed Google Scholar
Masoodi, M. et al. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat. Rev. Gastroenterol. Hepatol. 18, 835–856 (2021).
Article PubMed Google Scholar
Noureddin, M. et al. Serum identification of at-risk MASH: the metabolomics-advanced steatohepatitis fibrosis score (MASEF). Hepatology 79, 135–148 (2024).
Article PubMed Google Scholar
Harrison, S. A. et al. A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol. Hepatol. 5, 970–985 (2020).
Article PubMed Google Scholar
Johnson, K. et al. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: diagnostic and mechanistic relevance. JHEP Rep. 4, 100409 (2022).
Article PubMed Google Scholar
Harrison, S. A. et al. NIS2+TM, an optimisation of the blood-based biomarker NIS4® technology for the detection of at-risk NASH: a prospective derivation and validation study. J. Hepatol. 79, 758–767 (2023).
Article CAS PubMed Google Scholar