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

## TL;DR

This study shows that GPR83 protects against hearing loss caused by the drug ibrutinib, which is used to treat leukemia.

## Contribution

The novel finding is that GPR83 protects cochlear hair cells from ibrutinib-induced ototoxicity through AKT signaling and autophagy modulation.

## Key findings

- Ibrutinib causes hearing loss by damaging cochlear hair cells and inhibiting GPR83 and AKT pathways.
- GPR83 overexpression and Z-VAD-FMK treatment reduce ibrutinib-induced apoptosis and hearing loss.
- RNA sequencing suggests GPR83 protects hair cells by modulating autophagy.

## Abstract

Ibrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear.

This 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.

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.

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.