Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss

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.