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ORIGINAL RESEARCH article

Front. Med.

Sec. Translational Medicine

Volume 12 - 2025 | doi: 10.3389/fmed.2025.1579285

This article is part of the Research Topic Exploring Adverse Drug Reactions: Monitoring, Mechanism, Intervention, and Resolution View all articles

GPR83 protects cochlear hair cells against ibrutinib-induced hearing loss through AKT signaling pathways

Provisionally accepted
Yuhua Zhang Yuhua Zhang 1Yun Xiao Yun Xiao 1Yongjun Zhu Yongjun Zhu 1Lin Yan Lin Yan 1Nan Cheng Nan Cheng 1Yongjie Wei Yongjie Wei 1Yanghua Tian Yanghua Tian 2*Wei Cao Wei Cao 1*Jianming Yang Jianming Yang 1*
  • 1 Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
  • 2 Department of Neurology, Second Affiliated Hospital of Anhui Medical University, Anhui, China

The final, formatted version of the article will be published soon.

    Introduction: Ibrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear.Methods: This study investigated the impact of ibrutinib on hearing using HEI-OC1 cells, cochlear explants and C57BL/6J mice. We used RNA-sequences analysis to investigate the potential mechanisms of ibrutinib-induced ototoxicity. Mice received ibrutinib and auditory thresholds were assessed via auditory brainstem response testing; to assess the potential protective effects, we co-administered the caspase inhibitor Z-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) and monitored hearing.: Z-VAD-FMK mitigated ibrutinib-induced hearing loss by inhibiting apoptosis in auditory cells. Ibrutinib exposure resulted in cochlear hair cell (HC) damage and subsequent hearing loss by inhibiting the protein kinase B and G protein-coupled receptor 83 (GPR83) pathways. RNA sequencing suggested that GPR83 protects HCs by modulating autophagy. Z-VAD-FMK application and GPR83 overexpression attenuated ibrutinib-induced cochlear HC apoptosis and auditory decline. Conclusion: These findings confirm ibrutinib's ototoxicity and highlight the protective role of GPR83 in ibrutinib-induced hearing loss, supporting future clinical investigations into Z-VAD-FMK and GPR83 as interventions for ibrutinib or other chemotherapeutic drug-induced ototoxicity.

    Keywords: Ibrutinib, Hearing Loss, Hair cell, G protein-coupled receptor, Z-VAD-fmk, Apoptosis

    Received: 19 Feb 2025; Accepted: 18 Mar 2025.

    Copyright: © 2025 Zhang, Xiao, Zhu, Yan, Cheng, Wei, Tian, Cao and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yanghua Tian, Department of Neurology, Second Affiliated Hospital of Anhui Medical University, Anhui, China
    Wei Cao, Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
    Jianming Yang, Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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