Nuciferine Alleviates High-Fat Diet- and ApoE–/–-Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn. In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE^–/– mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc’s protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.