Resmetirom ameliorates fibrogenesis in hepatic stellate cells via thyroid hormone receptor alpha-fatty-acid amide hydrolase 1 signaling pathway

Resmetirom is a liver-directed, thyroid hormone receptor β (THRβ)-selective agonist approved for treating metabolic-associated steatohepatitis (MASH). While Resmetirom hepatocyte-specific effects are well-established, its impact on other hepatic cells, particularly hepatic stellate cells (HSCs), the main fibrogenic cells, remain unknown. Using animal models, immortalized cell lines, and primary murine and human HSCs, we combined pharmacological treatments with genetic manipulation of THRα and fatty acid amide hydrolase (FAAH) to examine the effects of Resmetirom. Resmetirom ameliorates MASH through actions in both hepatocytes and HSCs. The overexpression of solute carrier organic anion transporter family member 1B1(SLCO1β1) in both cell types increases the efficiency of Resmetirom. THRα expression is higher in HSCs than in hepatocytes in both human and murine cells. Resmetirom attenuates TGF-β1-induced HSC activation via THRα and increased FAAH expression and activity, while their inhibition prevents Resmetirom from reducing fibrotic marker expression and the elevated glycolytic activity typical of activated HSCs. These results uncover an unrecognized mechanism of action for Resmetirom, demonstrating that its antifibrotic efficacy extends beyond hepatocytes to include direct effects on HSCs via THRα and FAAH. These results may support the development of future therapeutic strategies aimed at THRα in HSC, in combination with existing approaches targeting hepatocyte THRβ.