PSMD2 mediates the degradation of CYP1A2 and promotes the progression of metabolic dysfunction-associated steatohepatitis.

Despite the well recognized downregulation of cytochrome P450 enzymes in metabolic dysfunction-associated steatohepatitis (MASH), the posttranscriptional mechanisms underlying this phenomenon are still not well understood. This study investigates the role of proteasomal degradation in the regulation of CYP1A2, a major hepatic P450 enzyme, during MASH progression. Using a high-fat diet-induced MASH mouse model and palmitic acid-treated hepatocytes model, we found that CYP1A2 protein levels were significantly decreased without corresponding changes in mRNA expression, indicating predominant posttranslational modification regulation. Mechanistically, we first identified 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) as a novel and crucial regulatory factor that dominates the posttranslational degradation of CYP1A2 during MASH development, and confirmed it functions as a key interacting protein mediating the accelerated proteasomal degradation of CYP1A2. Inhibition of proteasome activity with bortezomib or genetic silencing of PSMD2 effectively blocked CYP1A2 degradation and ameliorated hepatocyte lipid accumulation. Importantly, hepatocyte-specific knockdown of PSMD2 in vivo restored CYP1A2 expression and significantly alleviated MASH-associated pathologies, including hepatic steatosis, inflammation, and liver injury. Collectively, these findings establish PSMD2 as a novel and essential modulator that governs the posttranslational degradation of CYP1A2. Moreover, PSMD2 plays a critical role in the progression of MASH, highlighting its potential as a therapeutic target for this disease. SIGNIFICANCE STATEMENT: This study provides the first evidence that hepatocyte proteasome non-ATPase regulatory subunit 2 (PSMD2) drives metabolic dysfunction-associated steatohepatitis pathology by promoting CYP1A2 degradation and lipid accumulation. PSMD2 deficiency alleviates hepatic steatosis, reduces triglyceride and free fatty acid levels, and restores liver function. These findings establish PSMD2 as a critical regulator of lipid metabolism and hepatocyte integrity, positioning it as a promising therapeutic target for metabolic dysfunction-associated steatohepatitis intervention.