Nuciferine Alleviates\nHigh-Fat Diet- and ApoE<sup>–/–</sup>-Induced Hepatic\nSteatosis and Ferroptosis\nin NAFLD Mice via the PPARα Signaling Pathway

Nonalcoholic\nfatty liver disease (NAFLD) causes significant\nglobal\nmortality and healthcare costs with no recommended pharmacological\nintervention for clinical management. Nuciferine (Nuc) is an alkaloid\nwith aromatic rings, abundantly found in <i>Nelumbo nucifera\nGaertn</i>. In this study, we explored the protective mechanisms\nof Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat\ndiet (HFD) and healthy male ApoE<sup>–/–</sup> mice\nwere used to induce NAFLD and a hypercholesterolemia model. Nuc was\nadministered to the mice for four consecutive weeks from the ninth\nweek. Various assessments, including histopathology, RNA sequencing,\nlipid metabolism, and ferroptosis-related protein expression, showed\nthat Nuc alleviated hepatic steatosis and ferroptosis. We further\nshowed that Nuc improves fatty acid accumulation and ferroptosis through\nthe PPARα signaling pathway in mice and RSL3-treated AML-12\ncells. The PPARα inhibitor GW6471 blocked Nuc’s protective\neffects, leading to excess accumulation of iron ions. Thus, Nuc may\nbe a potential therapeutic agent for NAFLD.