Cellular and molecular mechanisms of Resmetirom in metabolic dysfunction-associated steatohepatitis (MASH): A transcriptomic profiling study

This study demonstrates that the thyroid hormone receptor-ß (THR-ß) agonist Resmetirom, the first FDA-approved anti-MASH drug, exerts potent therapeutic effects in a human relevant dietary mouse model of metabolic dysfunction–associated steatohepatitis (MASH) induced by fructose, palmitate, and cholesterol (FPC). Resmetirom treatment markedly improved hepatic steatosis, inflammation, and fibrosis, accompanied by reduced systemic inflammatory markers and hepatocyte death. Transcriptomic profiling revealed that Resmetirom profoundly reprograms hepatic gene expression, particularly suppressing pathways involved in lipid metabolism, inflammation, and multiple forms of programmed cell death, including apoptosis, pyroptosis, and necroptosis. These findings highlight a previously unrecognized role of THR-ß activation in regulating hepatocyte survival and inflammation, providing mechanistic insight into the multifaceted hepatoprotective effects of Resmetirom in MASH. Overall design: A diet-induced metabolic dysfunction–associated steatohepatitis (MASH) model using a fructose, palmitate, and cholesterol (FPC) diet. Mice were maintained on the FPC diet for 12 weeks, with therapeutic administration of Resmetirom (Rem) (5 mg/kg/day) initiated after 4 weeks of feeding and continued for an additional 8 weeks via intraperitoneal injection. The vehicle consisted of 0.5% carboxymethyl cellulose-sodium (CMC-Na) and 0.4% Tween-80.