Pathogenesis-Informed Phenotype-Guided Therapy for MASH: A Three-Axis Translational Framework Within the MASLD Spectrum

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), and its treatment landscape is rapidly moving from nonspecific liver fat reduction towards mechanism-based drug positioning. Since 2024, resmetirom and semaglutide have received U.S. Food and Drug Administration accelerated approval for non-cirrhotic MASH with moderate-to-advanced fibrosis, while tirzepatide, survodutide, and fibroblast growth factor 21 analogues have shown biopsy-based phase 2 or 2b efficacy signals. This narrative review organises approved and emerging pharmacotherapies within a pathogenesis-informed three-axis framework: the weight-insulin resistance-substrate load axis, the intrahepatic lipid reprogramming axis, and the inflammation-fibrosis transition and multi-axis integration axis. We further grade evidence maturity from regulatory or phase 3 histological evidence to phase 2 biopsy-based evidence and earlier imaging- or biomarker-based signals. This framework is intended to support phenotype-sensitive treatment positioning rather than a fixed therapeutic sequence. In particular, weight-centred treatment should not be assumed to apply to all patients, including normal-weight or lean MASH. Overall, future MASH therapy will likely depend on matching drug mechanisms, fibrosis stage, cardiometabolic phenotype, and treatment goals.