Artesunate alleviates cisplatin-induced nephrotoxicity by regulating tryptophan metabolism and inhibiting ferroptosis

Cisplatin (CIS)-induced nephrotoxicity is a dose-limiting adverse effect that hinders its clinical efficacy. Artesunate (ART) exerts well-documented anti-inflammatory and anti-oxidative effects, but its potential efficacy against CIS-induced nephrotoxicity remains poorly elucidated.

The renoprotective effects of ART were evaluated in a murine CIS-induced nephrotoxicity model and human HK-2 renal tubular epithelial cells. Renal function, histopathological injury, inflammation, and oxidative stress were evaluated. Untargeted renal metabolomics and transcriptomics were integrated to identify potential pathways, followed by targeted biochemical and molecular validation. Indoxyl sulfate rescue experiments were performed to investigate the functional relationship between tryptophan metabolism and ferroptosis.

ART treatment significantly ameliorated CIS-induced renal dysfunction, as evidenced by reduced SCr and BUN levels and attenuated histopathological damage. These functional improvements were accompanied by marked suppression of pro-inflammatory cytokines and restoration of redox balance. Integrated renal metabolomic and transcriptomic analyses revealed that ART exerts its protective effects primarily through modulation of tryptophan metabolism and ferroptosis pathway. Subsequent validation confirmed that ART inhibited ferroptosis by reducing Fe²⁺ accumulation, downregulating ACSL4 and FTL, and upregulating GPX4 and xCT. In HK-2 cells, indoxyl sulfate partially counteracted the cytoprotective and anti-ferroptotic effects of ART. Moreover, ART did not diminish CIS's antineoplastic effect in human cancer cells.

These findings demonstrate that ART alleviates CIS-induced nephrotoxicity by restoring tryptophan metabolic homeostasis and suppressing ferroptosis, positioning ART as a promising therapeutic candidate for preventing nephrotoxicity in patients undergoing CIS chemotherapy.