Resmetirom: The First Disease-Specific Treatment for MASH

Abstract

In 2023, the medical terminology for Nonalcoholic Fatty Liver Disease (NAFLD) and NA SteatoHepatitis (NASH) was updated to Metabolic Dysfunction-Associated SteatoticLiver Disease (MASLD) and MA SteatoHepatitis (MASH). This review highlights the critical epidemiological, pathophysiological, and therapeutic aspects of MASH, focusing on the novel treatment option, resmetirom. Resmetirom, a thyroid hormone receptor-beta (THR-β) agonist, specifically targets liver function to simulate localized hyperthyroidism, effectively reducing lipid accumulation and liver fibrosis without the systemic effects commonly associated with thyroid hormone therapy. Clinical trials, particularly the pivotal MAESTRO-NASH trial, have demonstrated significant improvements in liver health metrics, achieving primary endpoints by resolving MASH without worsening fibrosis and showing a favorable safety profile. This paper reviews the mechanism of action, efficacy, and safety of resmetirom, providing insight into its potential to change the therapeutic landscape for patients suffering from MASH.

Figure 1

The genomic effect of thyroid hormone on hepatocytes [–30]. T3 and T4 enter the hepatocyte through simple diffusion and cell membrane transporters. T4 is converted to T3 by deiodinase 1 (top left). THR-β is a member of the nuclear hormone receptor family, which binds to the thyroid response element (TRE) in the DNA. T3 binding to THR-β1 leads to transcription of several key genes, which affects (1) cholesterol metabolism, (2) lipid metabolism, (3) mitochondrial biogenesis and function, (4) hepatocyte proliferation and (5) carbohydrate metabolism. Abbreviations: Chole, cholesterol; DIO1, deiodinase 1; T3, tri-iodothyronine; T4, thyroxine; THR-β1, thyroid hormone receptor beta 1; TRE, thyroid response element.