Modulation of metabolic, inflammatory, fibrotic and cell death pathways by Resmetirom in metabolic dysfunction-associated steatohepatitis (MASH): A transcriptomic profiling study

Metabolic dysfunction–associated steatohepatitis (MASH) is a growing global burden with limited therapeutic options, and the mechanisms driving disease regression remain incompletely understood. Resmetirom, a selective thyroid hormone receptor-β (THR-β) agonist, has been approved for MASH, yet its molecular actions require further clarification. In this study, we employed a diet-induced mouse model of MASH using fructose–palmitate–cholesterol (FPC) feeding and evaluated the therapeutic efficacy of Resmetirom. Resmetirom (5 mg/kg/day) treatment significantly improved systemic and hepatic lipid profiles. Histological analyses demonstrated marked attenuation of hepatic steatosis, inflammation, and fibrosis, accompanied by reduced hepatic cell death. Transcriptomic profiling of liver tissues further revealed a robust Resmetirom-induced reprogramming of metabolic and inflammatory pathways, with prominent downregulation of gene networks governing lipid accumulation, immune activation, extracellular matrix remodeling, and multiple forms of programmed cell death. Collectively, these findings provide mechanistic insight into the multifaceted actions of Resmetirom and establish a comprehensive preclinical framework for understanding how THR-β activation ameliorates key pathological hallmarks of MASH. This work supports the therapeutic potential of Resmetirom and highlights critical molecular pathways that may inform future combination strategies for advanced metabolic liver disease.