{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:58:26Z","timestamp":1790866706116,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The recent approvals of resmetirom and semaglutide have marked a pivotal advance in the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, the modest fibrosis responses observed with current monotherapies and the persistence of substantial residual disease burden highlight the need for more comprehensive therapeutic strategies. Given the multifactorial pathogenesis of MASLD, combination therapy has emerged as a promising approach to simultaneously target metabolic dysfunction, hepatic steatosis, inflammation, and fibrogenesis. In this opinion article, we discuss the biological rationale for combination treatment and critically appraise the evidence from randomized clinical trials evaluating multidrug approaches in MASLD. While several studies have demonstrated encouraging improvements in hepatic and metabolic outcomes, others have failed to achieve their primary endpoints, underscoring that mechanistic complementarity does not necessarily translate into clinical synergy. We further review ongoing trials, including studies in advanced fibrosis and compensated cirrhosis, that are expected to shape the next phase of therapeutic development. Finally, we address key challenges related to patient selection, disease heterogeneity, treatment duration, safety, cost-effectiveness, and regulatory approval. We propose that the future of combination therapy in MASLD will likely rely on precision-medicine approaches that align therapeutic mechanisms with individual disease biology and stage.<\/jats:p>","DOI":"10.3390\/ijms27188368","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:23:56Z","timestamp":1790864636000},"page":"8368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Single Agents to Synergy: Redefining Therapeutic Strategies in MASLD"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-0742","authenticated-orcid":false,"given":"Lampros","family":"Chrysavgis","sequence":"first","affiliation":[{"name":"First Department of Internal Medicine, General Hospital Laiko, Medical School, National and Kapodistrian University of Athens, AgiouThoma 17, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3645-582X","authenticated-orcid":false,"given":"Evangelos","family":"Cholongitas","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, General Hospital Laiko, Medical School, National and Kapodistrian University of Athens, AgiouThoma 17, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","article-title":"Current status and future trends of the global burden of MASLD","volume":"35","author":"Miao","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1080\/17474124.2024.2374472","article-title":"From NAFLD to MASLD: What does it mean?","volume":"18","author":"Chrysavgis","year":"2024","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"156101","DOI":"10.1016\/j.metabol.2024.156101","article-title":"Prevalence, characteristics and outcomes of patients with metabolic and alcohol related\/associated liver disease (MetALD): A systematic review and meta-analysis","volume":"163","author":"Tampaki","year":"2025","journal-title":"Metabolism"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e70132","DOI":"10.1002\/edm2.70132","article-title":"Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Mechanisms, Clinical Implications and Therapeutic Advances","volume":"8","author":"Miller","year":"2025","journal-title":"Endocrinol. Diabetes Metab."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Liu, Y. (2025). The Emerging Challenge of Non-Cirrhotic MASLD-Related Hepatocellular Carcinoma: Etiology, Immunopathology, and Precision Oncology. Liver Cancer.","DOI":"10.1159\/000550163"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.semcancer.2023.04.010","article-title":"Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy","volume":"93","author":"Polyzos","year":"2023","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of metabolic dysfunction-associated steatotic liver disease","volume":"31","author":"Younossi","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100513","DOI":"10.1016\/j.jhepr.2022.100513","article-title":"Risk of further decompensation\/mortality in patients with cirrhosis and ascites as the first single decompensation event","volume":"4","author":"Balcar","year":"2022","journal-title":"JHEP Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12944-024-02108-x","article-title":"Updated mechanisms of MASLD pathogenesis","volume":"23","author":"Li","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/s41423-025-01307-5","article-title":"Immunopathogenic mechanisms and immunoregulatory therapies in MASLD","volume":"22","author":"He","year":"2025","journal-title":"Cell. Mol. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xu, S., Zhang, Z., Zhou, Z., and Guo, J. (2026). Immune Determinants of MASLD Progression: From Immunometabolic Reprogramming to Fibrotic Transformation. Biology, 15.","DOI":"10.3390\/biology15020148"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1111\/apt.17930","article-title":"Pathogenesis of MASLD and MASH\u2014Role of insulin resistance and lipotoxicity","volume":"59","author":"Bansal","year":"2024","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jurek, J.M., Zablocka-Sowinska, K., Clavero Mestres, H., Reyes Gutierrez, L., Camaron, J., and Auguet, T. (2025). The Impact of Dietary Interventions on Metabolic Outcomes in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Comorbid Conditions, Including Obesity and Type 2 Diabetes. Nutrients, 17.","DOI":"10.3390\/nu17071257"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sheikh, M.Y., Younus, M.F., Shergill, A., and Hasan, M.N. (2025). Diet and Lifestyle Interventions in Metabolic Dysfunction-Associated Fatty Liver Disease: A Comprehensive Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199625"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1111\/apt.70044","article-title":"Effects of a 12-Week Mediterranean-Type Time-Restricted Feeding Protocol in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Randomised Controlled Trial-The \u2018CHRONO-NAFLD Project\u2019","volume":"61","author":"Tsitsou","year":"2025","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1111\/dom.70617","article-title":"Weight Loss as a Determinant of Histological Improvement in Metabolic Dysfunction-Associated Steatotic Liver Disease in People With Obesity. A Systematic Review and Network Meta-Analysis of Randomised Clinical Trials","volume":"28","author":"Monami","year":"2026","journal-title":"Diabetes Obes. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s43856-025-00871-1","article-title":"The importance of patient engagement in the multimodal treatment of MASLD","volume":"5","author":"Boeckmans","year":"2025","journal-title":"Commun. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/j.cgh.2024.10.025","article-title":"Resolution of Metabolic Dysfunction-associated Steatohepatitis With No Worsening of Fibrosis After Bariatric Surgery Improves 15-year Survival: A Prospective Cohort Study","volume":"23","author":"Lassailly","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/dom.70173","article-title":"Metabolic bariatric surgery is associated with reduced adverse hepatic and extrahepatic outcomes, and lower all-cause mortality, in patients with steatotic liver disease","volume":"28","author":"Stupalkowska","year":"2026","journal-title":"Diabetes Obes. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1111\/apt.16335","article-title":"Systematic review with meta-analysis: Bariatric surgery reduces the incidence of hepatocellular carcinoma","volume":"53","author":"Ramai","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","volume":"362","author":"Sanyal","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_24","first-page":"e10446","article-title":"Pleiotropic Effects of Statins in the Light of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis","volume":"12","author":"Ahsan","year":"2020","journal-title":"Cureus"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14740\/gr1498","article-title":"Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions","volume":"15","author":"Kreidieh","year":"2022","journal-title":"Gastroenterol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98543","DOI":"10.5493\/wjem.v14.i4.98543","article-title":"Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis","volume":"14","author":"Tarar","year":"2024","journal-title":"World J. Exp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1001\/jamainternmed.2025.0115","article-title":"Statin Use and Risk of Hepatocellular Carcinoma and Liver Fibrosis in Chronic Liver Disease","volume":"185","author":"Choi","year":"2025","journal-title":"JAMA Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa2401755","article-title":"A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis","volume":"391","author":"Sanyal","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1038\/s41591-026-04479-3","article-title":"Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial","volume":"32","author":"Kaplan","year":"2026","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.jhep.2023.05.013","article-title":"A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease","volume":"79","author":"Lawitz","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1016\/S0140-6736(25)02114-2","article-title":"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","volume":"406","author":"Noureddin","year":"2025","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1038\/s41591-024-03018-2","article-title":"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: A randomized phase 2a trial","volume":"30","author":"Sanyal","year":"2024","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1016\/j.ymthe.2026.04.011","article-title":"A new liver-targeted agonist of thyroid hormone receptor beta resmetirom in treating MASLD\/MASH: From mechanism to therapy","volume":"34","author":"Liu","year":"2026","journal-title":"Mol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.cgh.2024.02.022","article-title":"Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH\/MASH and Type 2 Diabetes in a Randomized Phase 2 Study","volume":"23","author":"Harrison","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jhep.2024.12.006","article-title":"Safety and efficacy of GLP-1\/FGF21 dual agonist HEC88473 in MASLD and T2DM: A randomized, double-blind, placebo-controlled study","volume":"82","author":"Xiang","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jhep.2022.04.003","article-title":"Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial","volume":"77","author":"Alkhouri","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"(2024). The Liver Meeting: San Diego, California, Nov 15\u201319, 2024. Hepatology, 80, S1\u2013S2011.","DOI":"10.1097\/HEP.0000000000001077"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1038\/s41591-025-03722-7","article-title":"TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: The randomized phase 2a DUET trial","volume":"31","author":"Noureddin","year":"2025","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S2468-1253(25)00128-1","article-title":"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","volume":"10","author":"Wong","year":"2025","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/hep.31622","article-title":"Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH","volume":"73","author":"Loomba","year":"2021","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jhep.2020.02.027","article-title":"Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials","volume":"73","author":"Harrison","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"(2025). The Liver Meeting: 2025 Abstracts. Hepatology, 82, S1\u2013S2308.","DOI":"10.1097\/HEP.0000000000001493"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1016\/S0168-8278(26)00309-0","article-title":"LBO-005-YI The combination of senolytic drugs, dasatinib plus quercetin, reduces liver fibrosis in metabolic dysfunction\u2013associated steatohepatitis: A phase 2 randomized double-blind placebo controlled study: The TRUTH study","volume":"84","author":"Koning","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1111\/apt.70382","article-title":"Effects of Resmetirom on Metabolic-Dysfunction Associated Steatohepatitis in Patients With Weight Loss and\/or Diabetes Taking Glucagon-Like Peptide-1 Receptor Agonists and Other Diabetes Therapies: A Secondary Analysis of the MAESTRO-NASH Trial","volume":"62","author":"Noureddin","year":"2025","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/S0168-8278(26)00330-2","article-title":"OS-020 Effect of empagliflozin alone or combined with low-dose semaglutide on metabolic dysfunction-associated steatohepatitis and type 2 diabetes\u2014A histology-based randomized, placebocontrolled, double-blind phase 4 trial (COMBAT_T2_NASH)","volume":"84","author":"Kahl","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105889","DOI":"10.1016\/j.cct.2019.105889","article-title":"A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial","volume":"88","author":"Pedrosa","year":"2020","journal-title":"Contemp. Clin. Trials"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1097\/HEP.0000000000000439","article-title":"Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study","volume":"78","author":"Anstee","year":"2023","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0140-6736(25)01073-6","article-title":"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","volume":"406","author":"Noureddin","year":"2025","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1177\/00185787241278571","article-title":"Resmetirom","volume":"60","author":"Levien","year":"2025","journal-title":"Hosp. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/apt.18062","article-title":"Letter: Drug interaction in resmetirom times","volume":"60","author":"Zhou","year":"2024","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e001236","DOI":"10.1136\/bmjnph-2025-001236","article-title":"Prevalence of polypharmacy and associated side effects in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD): A systematic review and meta-analysis","volume":"8","author":"Armes","year":"2025","journal-title":"BMJ Nutr. Prev. Health"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/dom.13899","article-title":"Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis","volume":"22","author":"Avgerinos","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1111\/dom.15898","article-title":"Beneficial effect of oral semaglutide for type 2 diabetes mellitus in patients with metabolic dysfunction-associated steatotic liver disease: A prospective, multicentre, observational study","volume":"26","author":"Arai","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41392-024-02072-z","article-title":"Liver diseases: Epidemiology, causes, trends and predictions","volume":"10","author":"Gan","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.23276","article-title":"Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis","volume":"51","author":"Promrat","year":"2010","journal-title":"Hepatology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"154455","DOI":"10.1016\/j.metabol.2020.154455","article-title":"The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"115","author":"Koutoukidis","year":"2021","journal-title":"Metabolism"},{"key":"ref_60","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2024). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J. Hepatol., 81, 492\u2013542."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jhep.2026.02.015","article-title":"Cardiovascular risk in MASLD: What multiple lines of evidence reveal","volume":"85","author":"Sattar","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5009\/gnl250275","article-title":"Mortality and Cardiovascular Outcomes in Patients with MAFLD Compared with Patients with MASLD: A Systematic Review and Meta-Analysis","volume":"20","author":"Yang","year":"2026","journal-title":"Gut Liver"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(21)00213-0","article-title":"Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial","volume":"397","author":"Davies","year":"2021","journal-title":"Lancet"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S2213-8587(25)00226-8","article-title":"Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): A randomised, controlled, phase 3b trial","volume":"13","author":"Wharton","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Adinolfi, G., Milia, V., Dinkov, B., and Stavreva, G. (2026). Cardiovascular Outcomes Associated with Semaglutide in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Endocrines, 7.","DOI":"10.3390\/endocrines7010009"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jama.2023.24945","article-title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial","volume":"331","author":"Aronne","year":"2024","journal-title":"JAMA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1001\/jamainternmed.2025.6112","article-title":"Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial","volume":"186","author":"Horn","year":"2026","journal-title":"JAMA Intern. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(23)01200-X","article-title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial","volume":"402","author":"Garvey","year":"2023","journal-title":"Lancet"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1002\/oby.24332","article-title":"Tirzepatide for reduction of morbidity and mortality in adults with obesity: Rationale and design of the SURMOUNT-MMO trial","volume":"33","author":"Lam","year":"2025","journal-title":"Obesity"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e70003","DOI":"10.1111\/eci.70003","article-title":"Pharmacological treatment options for metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus: A systematic review","volume":"55","author":"Konings","year":"2025","journal-title":"Eur. J. Clin. Invest."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s13300-024-01550-5","article-title":"SGLT2 Inhibitors\u2014The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review","volume":"15","author":"Seidu","year":"2024","journal-title":"Diabetes Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3803\/EnM.2025.2786","article-title":"SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration","volume":"40","author":"Noh","year":"2025","journal-title":"Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.cmet.2026.02.018","article-title":"The many pathways driving liver inflammation in MASH","volume":"38","author":"Tilg","year":"2026","journal-title":"Cell Metab."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s44355-026-00061-3","article-title":"Diversity in metabolic dysfunction-associated steatotic liver disease: A framework for precision medicine","volume":"3","author":"Ko","year":"2026","journal-title":"npj Gut Liver"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"101713","DOI":"10.1016\/j.jhepr.2025.101713","article-title":"Integration of PNPLA3 and TM6SF2 genotypes provides incremental improvement in advanced fibrosis prediction among MASLD patients with type 2 diabetes mellitus","volume":"8","author":"Kim","year":"2026","journal-title":"JHEP Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/s41395-018-0041-8","article-title":"Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis","volume":"113","author":"Stickel","year":"2018","journal-title":"Am. J. Gastroenterol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/S0168-8278(26)00295-3","article-title":"GS-003 A PNPLA3 antisense oligonucleotide, AZD, for the treatment of MASH in I148M homozygous participants: Results from the phase 2b FORTUNA study","volume":"84","author":"Loomba","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"101645","DOI":"10.1016\/j.jhepr.2025.101645","article-title":"Validation of a data-driven clustering model for MASLD: Evidence from three large-scale Asian cohorts","volume":"8","author":"Zhou","year":"2026","journal-title":"JHEP Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1038\/s41591-024-03284-0","article-title":"Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease","volume":"30","author":"Jamialahmadi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3624","DOI":"10.1038\/s41591-024-03283-1","article-title":"Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease","volume":"30","author":"Raverdy","year":"2024","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Drygalski, K. (2025). Pharmacological Treatment of MASLD: Contemporary Treatment and Future Perspectives. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136518"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Zhou, J., Zhu, B., Bing, Z., Wang, T., and Zhao, Y. (2026). The Gut-Liver Axis in MASLD: From Host-Microbiome Crosstalk to Precision Therapeutics. Microorganisms, 14.","DOI":"10.3390\/microorganisms14020471"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Dong, X., Sun, W., Xu, H., Xie, Y., He, J., Liu, X., Liu, X., Ali, A., Chen, M., and Zhang, L. (2026). Ursodeoxycholic acid alleviates high-fat diet-induced liver injury by modulating gut microbiota-mediated bile acid metabolism: An integrated microbiota-metabolomics analysis. Front. Nutr., 13.","DOI":"10.3389\/fnut.2026.1714100"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3748\/wjg.v30.i4.290","article-title":"Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges","volume":"30","author":"Madir","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41392-025-02532-0","article-title":"Decoding organ fibrosis: Mechanistic insights and emerging therapeutic strategies","volume":"11","author":"Chen","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.jhep.2016.04.018","article-title":"Sinusoidal communication in liver fibrosis and regeneration","volume":"65","author":"Marrone","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1053\/j.gastro.2025.03.010","article-title":"Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis","volume":"169","author":"Kisseleva","year":"2025","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/hep.30834","article-title":"The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis","volume":"71","author":"Papatheodoridi","year":"2020","journal-title":"Hepatology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3748\/wjg.v28.i3.310","article-title":"Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link","volume":"28","author":"Chrysavgis","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1056\/NEJMoa2502242","article-title":"Efruxifermin in Compensated Liver Cirrhosis Caused by MASH","volume":"392","author":"Noureddin","year":"2025","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:32:52Z","timestamp":1790865172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":93,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188368"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188368","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}