Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss
Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss
复制标题
自噬依赖性铁死亡导致顺铂引起的听力损失
DOI：
10.1016/j.toxlet.2021.07.010
复制
发表时间：
2021-08-06
影响因子：
3.5
通讯作者：
Zheng, Yiqing
中科院分区：
文献类型：
--
作者：
Jian, Bingquan;Pang, Jiaqi;Zheng, Yiqing
顺铂所致听力损失是顺铂化疗的常见副作用，目前尚无临床治疗方法。毛细胞的凋亡被认为是顺铂耳毒性的主要原因，然而抑制细胞凋亡只能部分恢复顺铂所致的听力损失。因此，顺铂损伤所致的听觉细胞死亡尚需进一步研究。铁下垂是一种新的调节细胞死亡的形式，已被证明在顺铂毒性机制中发挥作用。在本研究中，我们观察了顺铂损伤后C57BL/6小鼠耳蜗铁前体的变化(脂质过氧化和抗氧化能力受损)，以验证铁下垂的诱导。在HEI-OC1细胞系中，我们观察到顺铂诱导的前铁链改变和激活的铁蛋白吞噬(特定的自噬途径)。使用氯喹，我们证实了自噬的阻断显著减轻了顺铂诱导的HEI-OC1细胞铁性下垂；因此，顺铂诱导的听觉细胞铁性下垂依赖于自噬的激活。此外，铁下垂抑制剂铁抑素-1和铁络合剂去铁胺显著减轻顺铂对HEI-OC1细胞和耳蜗外植体的细胞毒作用。此外，使用铁抑素-1药物抑制铁下垂显著减少顺铂损伤后C57BL/6小鼠的听觉细胞损失，尤其是减轻听力损失。综上所述，这些发现表明自噬依赖型铁下垂在顺铂所致听力损失的机制中起着综合作用。(C)爱思唯尔出版的《2021年》。
Cisplatin-induced hearing loss is a common side effect of cisplatin chemotherapy, for which clinical therapy remains unavailable. Apoptosis of hair cells is considered the primary cause of cisplatin-induced ototoxicity; however, inhibiting apoptosis can only partially restore cisplatin-induced hearing loss. Therefore, auditory cell death caused by cisplatin damage requires further study. Ferroptosis, a novel form of regulated cell death, has been shown to play a role in the mechanism of cisplatin toxicity. In this study, we observed proferroptotic alterations (lipid peroxidation and impaired antioxidant capacity) in the cochleae of C57BL/6 mice after cisplatin damage, verifying the induction of ferroptosis. Using the HEI-OC1 cell line, we observed that cisplatin induced proferroptotic alterations and activated ferritinophagy (specific autophagy pathway). Employing chloroquine, we confirmed that the blockage of autophagy remarkably alleviated cisplatin-induced ferroptosis in HEI-OC1 cells; therefore, the induction of ferroptosis in cisplatin-treated auditory cells was dependent on the activation of autophagy. In addition, the ferroptosis inhibitor ferrostatin-1 and iron chelator deferoxamine significantly attenuated cisplatin-induced cytotoxicity in HEI-OC1 cells and cochlear explants. Moreover, pharmacologically inhibiting ferroptosis using ferrostatin-1 significantly decreased the auditory cell loss and, notably, attenuated hearing loss in C57BL/6 mice after cisplatin damage. Collectively, these findings indicate that autophagy-dependent ferroptosis plays an integrated role in the mechanism of cisplatin-induced hearing loss. (c) 2021 Published by Elsevier B.V.