E3 Ubiquitin Ligases in MASH-Associated Liver Fibrosis: Mechanisms and Therapeutic Opportunities.

Metabolic dysfunction-associated steatohepatitis (MASH) is a major cause of progressive liver fibrosis and can ultimately lead to cirrhosis and hepatocellular carcinoma (HCC). MASH-associated liver fibrosis develops through a complex interplay among lipotoxic hepatocyte injury, oxidative and endoplasmic reticulum stress, inflammatory macrophage activation, hepatic stellate cell (HSC) activation and excessive extracellular matrix (ECM) deposition. E3 ubiquitin ligases, which determine substrate specificity within the ubiquitin-proteasome system, have emerged as important regulators of these processes. By controlling protein stability, signalling complex formation, inflammatory responses, cellular stress, autophagy, ferroptosis and intercellular communication, E3 ubiquitin ligases can influence both fibrosis progression and resolution. Because E3 ubiquitin ligases may exert pro-fibrotic or anti-fibrotic effects depending on the substrate, cell types, metabolic environment and disease stage, their therapeutic targeting requires disease- and cell type-specific strategies. In this review, we summarize the roles of E3 ubiquitin ligases in MASH-related liver fibrosis, with a particular focus on their functions in hepatocytes, HSCs, macrophages and other liver-resident cells. We also discuss emerging therapeutic approaches, including direct modulation of E3 ubiquitin ligase, proteolysis-targeting chimeras (PROTACs), molecular glues and cell type-specific delivery platforms.