TRIM25‐Mediated INSIG1 Ubiquitination Promotes MASH Progression Through Reprogramming Lipid Metabolism

The global incidence of Metabolic dysfunction-associated steatohepatitis (MASH) is increasing, highlighting the urgent need for new treatment strategies. This study aimed to investigate the involvement of tripartite motif-containing 25 (TRIM25) in MASH progression and explore the therapeutic potential of the TRIM25 inhibitor, C₂₇H₂₆N₂O₄S. Functional studies reveal that TRIM25 promoted lipid accumulation and inflammation by ubiquitinating and degrading insulin-induced gene 1 (INSIG1), thereby enhancing the nuclear translocation of sterol regulatory element-binding protein 2 (SREBP2) and upregulating lipid biosynthesis genes. In vivo experiments using TRIM25 knockout mice demonstrated that TRIM25 deletion ameliorated MASH progression, reduced fibrosis, and decreased inflammatory cell infiltration. It identifies C₂₇H₂₆N₂O₄S as a specific inhibitor of TRIM25. C₂₇H₂₆N₂O₄S effectively decreased INSIG1 ubiquitination and attenuated lipid accumulation in the hepatocytes. To enhance the hepatic delivery of C₂₇H₂₆N₂O₄S, it utilizes exosomes derived from hepatic stellate cells (HSC-EVs). Biodistribution analysis confirmed that the HSC-EVs preferentially accumulated in the liver. In a MASH mouse model, HSC-EV-encapsulated C₂₇H₂₆N₂O₄S (C₂₇H₂₆N₂O₄S@HSC-EV) significantly reduced hepatic lipid accumulation and alleviated MASH severity and fibrosis. This study highlights the critical regulatory role of TRIM25 in MASH and presents C₂₇H₂₆N₂O₄S@HSC-EV as a promising therapeutic approach for MASH treatment.