Hepatocyte‐Centered Regulation of MASH Fibrosis: From Animal Models to Molecular Mechanisms and Targeted Therapies

ABSTRACT Metabolic dysfunction‐associated steatohepatitis (MASH) is a major driver of liver fibrosis, with fibrosis stage being the strongest predictor of clinical outcomes. Recent advances have redefined MASH pathogenesis as a hepatocyte‐centered process in which metabolically stressed hepatocytes actively regulate fibrogenesis through direct communication with hepatic stellate cells (HSCs). This review integrates findings from metabolically relevant animal models, particularly the fructose–palmitate–cholesterol model, and in vitro systems to highlight how distinct metabolic insults reprogram hepatocytes to secrete profibrotic mediators, including Indian hedgehog, osteopontin, meteorin, bone morphogenetic protein 8B, and Jagged1, as well as metabolite‐ and vesicle‐mediated signals such as orotic acid and small extracellular vesicles. These hepatocyte‐derived factors directly activate HSCs and sustain fibrogenesis, with convergent pathways such as the cholesterol–TAZ–IHH axis emerging as central drivers. In parallel, hepatocytes also produce antifibrotic signals, including SERPINA3, ANGPTL6, and TrkB‐dependent pathways, which counterbalance HSC activation but are diminished during disease progression. Building on these mechanistic insights, hepatocyte‐targeted small interfering RNA therapies, particularly GalNAc‐conjugated approaches targeting key regulators such as TAZ and JAG1, have demonstrated robust antifibrotic efficacy in preclinical and humanized models. Together, this review establishes a hepatocyte‐centered framework for MASH fibrosis and highlights precision gene‐silencing strategies as promising therapeutic avenues to disrupt hepatocyte‐driven HSC activation and fibrotic remodeling.