journal article·2024-10Open access

FOXO1‐NCOA4 Axis Contributes to Cisplatin‐Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy

Xue Wang, Lei Xu, Yu Meng, Fang Chen, Jinzhu Zhuang, Man Wang, Weibin An, Yuechen Han, Bo Chu, Renjie Chai, Wenwen Liu, Haibo Wang

Advanced Science· Volume 11· Issue 40

Abstract

Abstract Mammalian cochlea spiral ganglion neurons (SGNs) are crucial for sound transmission, they can be damaged by chemotherapy drug cisplatin and lead to irreversible sensorineural hearing loss (SNHL), while such damage can also render cochlear implants ineffective. However, the mechanisms underlying cisplatin‐induced SGNs damage and subsequent SNHL are still under debate and there is no currently effective clinical treatment. Here, this study demonstrates that ferroptosis is triggered in SGNs following exposure to cisplatin. Inhibiting ferroptosis protects against cisplatin‐induced SGNs damage and hearing loss, while inducing ferroptosis intensifies these effects. Furthermore, cisplatin prompts nuclear receptor coactivator 4 (NCOA4)‐mediated ferritinophagy in SGNs, while knocking down NCOA4 mitigates cisplatin‐induced ferroptosis and hearing loss. Notably, the upstream regulator of NCOA4 is identified and transcription factor forkhead box O1 (FOXO1) is shown to directly suppress NCOA4 expression in SGNs. The knocking down of FOXO1 amplifies NCOA4‐mediated ferritinophagy, increases ferroptosis and lipid peroxidation, while disrupting the interaction between FOXO1 and NCOA4 in NCOA4 knock out mice prevents the cisplatin‐induced SGN ferroptosis and hearing loss. Collectively, this study highlights the critical role of the FOXO1‐NCOA4 axis in regulating ferritinophagy and ferroptosis in cisplatin‐induced SGNs damage, offering promising therapeutic targets for SNHL mitigation.
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Research context

OpenAlex topics: Cancer-related molecular mechanisms research · Circular RNAs in diseases · FOXO transcription factor regulation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Otolaryngology‐Head and Neck Surgery Shandong Provincial ENT Hospital Shandong University Jinan 250022 China

Shandong Institute of Otorhinolaryngology Jinan 250022 China

Department of Cell Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan 250012 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 210096 China

Co‐Innovation Center of Neuroregeneration Nantong University Nantong 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 610072 China

Southeast University Shenzhen Research Institute Shenzhen 518063 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Natural Science Foundation of Jiangsu Province · Science and Technology Department of Sichuan Province

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