Nuciferine protects against folic acid‐induced acute kidney injury by inhibiting ferroptosis

<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Acute kidney injury is a common clinical problem with no definitive or specific treatment. Therefore, the molecular mechanisms of acute kidney injury must be fully understood to develop novel treatments. Nuciferine, a major bioactive compound isolated from the lotus leaf, possesses extensive pharmacological activities. Its effect on folic acid‐induced acute kidney injury, however, remains unknown. Here, we aimed to clarify the pharmacological effects of nuciferine and its mechanisms of action in acute kidney injury.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>The effects of nuciferine on folic acid‐induced acute kidney injury in mice were investigated. HK‐2 human proximal tubular epithelial cells and HEK293T HEK cells were used to evaluate the protective effect of nuciferine on RSL3‐induced ferroptosis.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Nuciferine treatment mitigated the pathological alterations, ameliorated inflammatory cell infiltration and improved kidney dysfunction in mice with folic acid‐induced acute kidney injury. In HK‐2 and HEK293T cells, nuciferine significantly prevented RSL3‐induced ferroptotic cell death. Mechanistically, nuciferine significantly inhibited ferroptosis by preventing iron accumulation and lipid peroxidation <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Moreover, knockdown of glutathione (GSH) peroxidase 4 (GPX4) abolished the protective effect of nuciferine against ferroptosis.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>Nuciferine ameliorated renal injury in mice with acute kidney injury, perhaps by inhibiting the ferroptosis. Nuciferine may represent a novel treatment that improves recovery from acute kidney injury by targeting ferroptosis.</jats:p></jats:sec>