Frontiers in Medicine (Apr 2025)

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

  • Yuhua Zhang,
  • Yun Xiao,
  • Yongjun Zhu,
  • Lin Yan,
  • Nan Cheng,
  • Yongjie Wei,
  • Yanling Zhang,
  • Yanghua Tian,
  • Wei Cao,
  • Jianming Yang

DOI
https://doi.org/10.3389/fmed.2025.1579285
Journal volume & issue
Vol. 12

Abstract

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IntroductionIbrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear.MethodsThis study investigated the impact of ibrutinib on hearing using HEI-OC1 cells, cochlear explants and C57BL/6 J 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.ResultsZ-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.ConclusionThese 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.

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