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<p>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.</p>

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Phenothiazine alleviates cisplatin-mediated acute kidney injury by inhibiting ferroptosis

  • 期刊论文

  • 发表日期：

    2026年1月23日

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  • Xue Sun,
  • Yang Chen,
  • Chong Wei,
  • Junyi Shao,
  • Jingshu Min,
  • Feiyang Zhao,
  • Chaoyi Xia

摘要

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.