Resmetirom as a Selective Thyroid Hormone Receptor-Beta Agonist in the Management of NAFLD/NASH and MASLD/MASH: A Narrative Literature Review

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health burden associated with fibrosis progression, cirrhosis, hepatocellular carcinoma, and increased cardiovascular risk. Despite the increasing prevalence of MASLD/MASH, effective pharmacological treatment options have historically been limited. Resmetirom, a selective thyroid hormone receptor-beta (THR-beta) agonist, has recently emerged as a novel liver-directed therapy targeting key metabolic mechanisms involved in disease progression. This narrative literature review aimed to evaluate the mechanism of action, clinical efficacy, safety profile, and therapeutic potential of resmetirom in the management of MASLD/MASH. A structured literature search was conducted using PubMed, ScienceDirect, and SpringerLink to identify relevant studies published between 2015 and 2025. Eligible publications included randomized controlled trials, extension studies, systematic reviews, meta-analyses, clinical practice guidance documents, and regulatory reports evaluating the efficacy and safety of resmetirom.
Current evidence indicates that resmetirom selectively activates hepatic THR-beta, promoting fatty acid β-oxidation, enhancing mitochondrial function, reducing hepatic triglyceride accumulation, and improving cholesterol metabolism. Phase II and phase III clinical trials, including the pivotal MAESTRO-NASH trial, demonstrated significant reductions in liver fat content, improvements in liver enzymes and atherogenic lipid parameters, and favorable histological outcomes, including MASH resolution and fibrosis improvement. Resmetirom also consistently reduced low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B, suggesting potential cardiometabolic benefits beyond improvements in liver histology. The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms. In conclusion, resmetirom represents a significant therapeutic advancement in MASLD/MASH and the first liver-directed pharmacological therapy approved for selected patients with non-cirrhotic MASH and moderate-to-advanced fibrosis. Although long-term outcome data remain limited, current evidence supports its role as a promising metabolic-based treatment for improving both hepatic and cardiometabolic outcomes.