Cisplatin is a well-known and widely used anticancer drug with high therapeutic efficacy in solid tumors; however, side effects are common with its use. Because cisplatin can be retained in the cochlea, ototoxicity leading to hearing loss limits its clinical applications. Here, we report that Nrf2 knockout (KO) strongly increased cisplatin resistance in HEI-OC1 cells, which are immortalized cells from the murine organ of Corti. The underlying mechanism of this phenomenon was uncovered, and an important novel therapeutic target for combating cisplatin-induced hearing loss was identified. Preliminary investigations determined that Nrf2 KO markedly decreased TfR1 protein levels and increased GPX4 protein levels. Thus, ferroptosis may protect organisms from cisplatin-induced cell death. Furthermore, Nrf2 KO cells were resistant to the classical ferroptosis inducers RSL3 and erastin, providing solid evidence that Nrf2 KO inhibits ferroptosis and that knocking out Nrf2 may be a new clinical strategy to prevent cisplatin-induced hearing loss.
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机译：顺铂是一种众所周知且应用广泛的抗癌药物，在实体瘤中具有很高的治疗效果;然而，副作用在它的使用中很常见。因为顺铂可以保留在耳蜗中，所以导致听力损失的耳毒性限制了其临床应用。在这里，我们报道了 Nrf2 敲除 （KO） 强烈增加了 HEI-OC1 细胞的顺铂耐药性，HEI-OC1 细胞是来自 Corti 小鼠器官的永生化细胞。揭示了这种现象的潜在机制，并确定了对抗顺铂诱导的听力损失的重要新治疗靶点。初步研究确定 Nrf2 KO 显著降低 TfR1 蛋白水平并增加 GPX4 蛋白水平。因此，铁死亡可以保护生物体免受顺铂诱导的细胞死亡。此外，Nrf2 KO 细胞对经典的铁死亡诱导剂 RSL3 和 erastin 具有抗性，提供了确凿的证据，证明 Nrf2 KO 抑制铁死亡，敲除 Nrf2 可能是预防顺铂诱导的听力损失的新临床策略。
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