RNF2 Modulates Lipid Metabolism and Inflammation in Alcohol-associated Liver Disease by Interacting with USP7

Alcohol-associated liver disease (ALD) is a widely prevalent chronic liver disease caused by alcohol overconsumption. However, the pathogenesis of ALD is complex and has not been fully elucidated. Ring finger protein 2 (RNF2) is associated with the occurrence and development of hepatocellular carcinoma (HCC), but its function in ALD has not been explored. In this study, we investigated the role of RNF2 in ALD and its underlying mechanisms. In vivo, an ALD model was established and adeno-associated virus (AAV8-shRNA-RNF2) was used to knock down RNF2. Liver injury, hepatic steatosis, and inflammation were assessed and functional studies were conducted in AML-12 cells and macrophages. The study found that hepatic-specific RNF2 knockdown attenuated EtOH-induced liver steatosis and inflammation. Furthermore, RNF2 knockdown significantly alleviated EtOH-mediated lipid accumulation and inflammation. Additionally, RNF2 interacted with ubiquitin-specific peptidase 7 (USP7) and regulated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway. Importantly, inhibition of USP7 or PI3K/AKT signaling pathway suppressed lipid accumulation and inflammation in the ALD model. Our research demonstrated that RNF2 had a novel function of regulating lipid metabolism and inflammation in ALD through its interaction with USP7 and modulation of the PI3K/AKT signaling pathway.