This study provides the first evidence that hepatocyte PSMD2 drives MASH 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 MASH intervention.