Impact of Resmetirom on Liver Histology and Metabolic Profiles in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Across the Spectrum of Thyroid Status: A Systematic Review

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to metabolic syndrome and to thyroid dysfunction, particularly hypothyroidism, which may weaken Thyroid Hormone Receptor-β (THR-β) signaling in hepatocytes. Resmetirom, an oral liver-directed THR-β agonist, is the first drug approved for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis. Objective: To synthesize the effects of resmetirom on liver histology, hepatic fat, lipid and other metabolic parameters, thyroid indices and safety in adults with MASLD, with attention to thyroid status. Methods: PubMed, Scopus, Web of Science, the Cochrane Library and ClinicalTrials.gov were searched from inception to March 2025. Randomized phase 2 and phase 3 trials of resmetirom in adults with MASLD or MASH were eligible. The review followed PRISMA 2020, risk of bias was assessed with Cochrane RoB 2 and results were synthesized narratively because of heterogeneity in populations and endpoints. Results: Three double-blind, placebo-controlled trials were included: a phase 2 trial (n = 125), MAESTRO-NAFLD-1 (n = 972 double-blind) and MAESTRO-NASH (n = 966). Resmetirom reduced hepatic fat on MRI-PDFF in all three (phase 2, week 12: −32.9% vs −10.4%). In MAESTRO-NASH, MASH resolution without worsening of fibrosis at week 52 occurred in 25.9% (80 mg) and 29.9% (100 mg) versus 9.7% with placebo and fibrosis improved by at least one stage in 24.2% and 25.9% versus 14.2%. LDL cholesterol fell by 13.6% to 16.3% at week 24, with parallel reductions in apolipoprotein B and triglycerides. Free T4 declined by roughly 16% to 21% while TSH and free T3 changed little, irrespective of levothyroxine use. Adverse events were mainly mild-to-moderate diarrhea and nausea. Participants with untreated hypothyroidism were excluded and efficacy was not reported by thyroid-status subgroup. Conclusion: Resmetirom improves liver fat, histology and atherogenic lipids with an acceptable safety profile in MASLD/MASH. Evidence for patients with stable, treated hypothyroidism is reassuring for thyroid-axis safety but does not yet establish thyroid-specific efficacy; dedicated analyses in hypothyroid cohorts and longer follow-up are needed.