In this study, we explored the protective effects and related mechanisms of Empa in the PA-induced lipotoxicity model and confirmed the significance of CAMKK2/AMPK-regulated FoxO3a and Nrf2 co-mediated antioxidant systems in PA-induced lipotoxicity, finding that the CAMKK2/AMPK pathway may be a therapeutic target for NAFLD. This evidence concerns the gene CAMKK2 and metabolic dysfunction-associated steatotic liver disease.