Abstract

Cisplatin is a first-line chemotherapeutic agent for various tumors; however, its clinical utility is substantially limited by the risk of cisplatin-induced acute kidney injury (AKI). Since inhibition of ferroptosis effectively mitigates cisplatin toxicity, we aimed to expand the therapeutic window of cisplatin by identifying potent ferroptosis inhibitors. High-throughput quantitative cell imaging-based screening of an FDA-approved drug library identified phenothiazine (PTZ) as a promising ferroptosis inhibitor. We further validated the ferroptosis-inhibitory activity of PTZ under both GPX4 inhibition and cystine deprivation conditions. Notably, PTZ administration markedly attenuated cisplatin-induced AKI and dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mouse models. These findings indicate that PTZ holds clinical potential for reducing cisplatin-associated nephrotoxicity, thereby broadening the therapeutic applicability of cisplatin, as well as for treating IBD. Given its robust anti-ferroptosis effects, PTZ may also provide therapeutic benefits in other ferroptosis-related pathologies. Collectively, this study identifies PTZ as a promising lead compound for the development of ferroptosis-targeted therapeutics.