Licochalcone A mitigates cisplatin-induced nephrotoxicity by inhibiting ferroptosis and mitochondrial dysfunction via the Nrf2/GPX4 axis

Background Cisplatin-induced nephrotoxicity is a major dose-limiting complication of chemotherapy. However, effective protective strategies remain limited. Licochalcone A (LicoA), a flavonoid isolated from Glycyrrhiza inflata, exhibits multi-target bioactivity against oxidative stress, inflammation, and metabolic disorders. Methods In vivo murine cisplatin-induced model and in vitro HK-2 cells were employed. HE/Masson staining, renal function, oxidative stress, ferroptosis markers (Fe 2+ , GSH, MDA, lipid peroxidation), and mitochondrial health were assessed. Mechanistic studies were conducted using metabolomic approaches, molecular docking, cellular thermal shift assay, Western blot, immunofluorescence, and Nrf2-knockdown assays. Results LicoA significantly ameliorated cisplatin-induced renal dysfunction and attenuated the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), as evidenced by reduced tubular injury and fibrosis. Metabolomic analysis revealed that LicoA restored energy metabolism and glutathione homeostasis. LicoA effectively alleviated cisplatin-induced ferroptosis by inhibiting Fe 2+ accumulation, reducing lipid peroxidation, restoring cellular redox homeostasis, and consequently diminishing membrane blistering. Molecular docking and cellular thermal shift assay confirmed the binding affinity between LicoA and both Nrf2 and GPX4. Crucially, Nrf2 knockdown abolished the protective effects of LicoA, demonstrating the essential role of the Nrf2 pathway. Conclusion LicoA alleviated cisplatin-induced renal injury by activating the Nrf2/GPX4 axis, thereby suppressing ferroptosis and mitigating mitochondrial damage. These findings highlight the therapeutic potential of LicoA in preventing cisplatin nephrotoxicity and impeding the AKI-to-CKD transition.