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

BACKGROUND AND PURPOSE: Acute kidney injury (AKI) is a common clinical problem with no definitive or specific treatment. Therefore, the molecular mechanisms of AKI must be elicited to develop novel treatments. Nuciferine, a major bioactive compound isolated from the lotus leaf, possesses extensive pharmacological activities. Its effect on folic acid (FA)-induced AKI, however, remains unknown. Here we aimed to clarify the pharmacological effects of nuciferine and underlying mechanisms in AKI.

EXPERIMENTAL APPROACH: The effects of nuciferine on FA-induced AKI in mice were investigated. HK-2 human proximal tubular epithelial cells and HEK293T human embryonic kidney cells were used to evaluate the protective effect of nuciferine on RSL3-induced ferroptosis.

KEY RESULTS: Nuciferine treatment mitigated the pathological alterations, ameliorated inflammatory cell infiltration and improved kidney dysfunction in mice with FA-induced AKI. 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 in vitro and in vivo. Moreover, knockdown of glutathione peroxidase 4 (GPX4) abolished the protective effect of nuciferine against ferroptosis.

CONCLUSIONS AND IMPLICATIONS: Nuciferine ameliorated renal injury in mice with AKI, perhaps by inhibiting the ferroptosis. Nuciferine may represent a novel treatment that improves recovery from AKI by targeting ferroptosis.