Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss. (10th October 2021)

• Record Type: Journal Article
• Authors: Jian, Bingquan; Pang, Jiaqi; Xiong, Hao; Zhang, Weijian; Zhan, Ting; Su, Zhongwu; Lin, Hanqing; Zhang, Huasong; He, Wuhui; Zheng, Yiqing
• Is Part Of: Toxicology letters. Volume 350(2021)
• Page Start: 249
• Page End: 260
• Publication Date: 2021-10-10
• Subjects: OHC outer hair cell -- ROS reactive oxygen species -- ABR auditory brainstem response -- RCD regulated cell death -- Fer-1 ferrostatin-1 -- GPX4 glutathione peroxidase 4 -- SLC7A11 solute carrier family 7 member 11 -- GSH glutathione -- MDA malondialdehyde -- DFO deferoxamine -- CQ chloroquine -- CCK8 cell counting kit-8 -- 4-HNE 4-hydroxynonenal -- FTH heavy chain of ferritin -- LAMP-1 lysosomal-associated membrane protein 1 -- NCOA4 nuclear receptor coactivator 4; Cisplatin -- Hearing loss -- Ferroptosis -- Autophagy -- Otoprotective strategy; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.07.010
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Ferroptosis is one of the auditory cell death forms under cisplatin injury. The activation of the specific autophagy pathway, ferritinophagy, is required for ferroptosis execution in HEI−OC1 cells. Ferroptosis inhibitor ameliorates the hearing impairment in C57BL/6 mice and outer hair cells loss after cisplatin exposure. Abstract: 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.