TRIM29-dependent AKR1B10 degradation ameliorates MASH.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent and life-threatening liver disease with limited effective therapies, necessitating the urgent identification of previously unidentified molecular targets and effective pharmacologic agents. This study identifies aldo-keto reductase family 1 member B10 (AKR1B10) as the MASH hallmark, showing elevated expression in patient tissues and serum, correlating strongly with disease severity. Genetic ablation of <i>Akr1b10</i> in mice significantly attenuated high-fat/high-cholesterol (HFHC) diet-induced steatosis, inflammation, and fibrosis. Mechanistically, we found that tripartite motif protein 29 (TRIM29) functions as an E3 ubiquitin ligase that directly binds AKR1B10, promoting its ubiquitination and proteasomal degradation, which ameliorates MASH progressions. Furthermore, the natural compound coptisine (COP) allosterically facilitated TRIM29-AKR1B10 interaction, accelerating AKR1B10 degradation and showing improved efficacy in MASH mice. Moreover, <i>Trim29</i> overexpression enhances COP-mediated symptoms alleviation. Our findings delineate the TRIM29/AKR1B10 axis as a druggable signaling pathway and identify COP as a promising therapeutic candidate for MASH.