Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice

Ziyi Liu; Hanbing Zhang; Guodong Hong; Xiuli Bi; Jun Hu; Tiancheng Zhang; Yachun An; Na Guo; Fengyue Dong; Yu Xiao; Wen Li; Xiaoxu Zhao; Bo Chu; Siwei Guo; Xiaohan Zhang; Renjie Chai; Xiaolong Fu

doi:10.1016/j.ymthe.2024.02.029

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice

Mol Ther. 2024 Feb 27:S1525-0016(24)00098-4. doi: 10.1016/j.ymthe.2024.02.029. Online ahead of print.

Authors

Ziyi Liu¹, Hanbing Zhang², Guodong Hong¹, Xiuli Bi¹, Jun Hu³, Tiancheng Zhang³, Yachun An⁴, Na Guo¹, Fengyue Dong⁴, Yu Xiao⁴, Wen Li¹, Xiaoxu Zhao¹, Bo Chu⁵, Siwei Guo⁴, Xiaohan Zhang¹, Renjie Chai⁶, Xiaolong Fu⁷

Affiliations

¹ Medical Science and Technology Innovation Center, Institute of Brain Science and Brain-inspired Research, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
² Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, Shandong 250012, China.
³ Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁴ School of Life Science, Shandong University, Qingdao, Shandong 266237, China.
⁵ Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250102, China.
⁶ Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China; Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing 100081, China; Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Southeast University Shenzhen Research Institute, Shenzhen, Guangdong 518063, China. Electronic address: renjiac@seu.edu.cn.
⁷ Medical Science and Technology Innovation Center, Institute of Brain Science and Brain-inspired Research, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China. Electronic address: 210112@sdfmu.edu.cn.

PMID: 38414247
DOI: 10.1016/j.ymthe.2024.02.029

Abstract

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4^-/- mice. However, Fsp1^-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Keywords: Fsp1; Gpx4; cisplatin-induced ototoxicity; ferroptosis; luteolin; transferrin.