Therapeutic Mechanisms of Resmetirom and Semaglutide in MASLD/MASH: A Review of Inflammatory and Fibrotic Metabolites.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease, and its progressive inflammatory phenotype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis. These processes are closely linked to altered metabolite networks, including lipotoxic lipids, oxidized lipid mediators, bile acids, amino acids, acylcarnitines, redox-related metabolites, gut-derived metabolites, and extracellular matrix remodeling products. The recent introduction of resmetirom and semaglutide for MASH with moderate-to-advanced fibrosis provides two complementary models for interpreting these networks. Resmetirom, a liver-directed thyroid hormone receptor-β agonist, primarily enhances intrahepatic lipid handling, mitochondrial fatty acid metabolism, cholesterol turnover, and lipoprotein remodeling. Through this "inside-out" mechanism, resmetirom may reduce hepatocyte lipotoxic stress and secondarily attenuate inflammatory and fibrogenic signaling. Semaglutide, a glucagon-like peptide-1 receptor agonist, mainly acts through systemic metabolic unloading by reducing energy intake, body weight, insulin resistance, and adipose-liver substrate flux. Through this "outside-in" mechanism, semaglutide may improve the hepatic metabolite environment indirectly. However, histological improvement does not by itself establish causal metabolite mediators, and many specific metabolite-level mechanisms remain incompletely defined in human MASH. This review summarizes metabolite networks linked to inflammation and fibrosis in MASLD/MASH, compares the metabolic implications of resmetirom and semaglutide, and discusses how therapeutic metabolomics may support biomarker discovery, patient stratification, and precision pharmacotherapy.