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

Abstract 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.