Comparative pharmacodynamic analysis of resmetirom, semaglutide and obeticholic acid in translational mouse models of MASH

Aim: This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research. Methods: The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed. Results: In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only. Conclusions: Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.