Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accum
Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission. Methods We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice. Results We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation. Conclusions The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD. Graphical abstract
