Formyl peptide receptor 2 (FPR2) mediates cisplatin-induced cochlear inflammation and hair cell apoptosis.

Despite its efficacy in cancer treatment, cisplatin is significantly limited by its debilitating ototoxicity and the poorly understood mechanisms underlying this adverse effect. This study investigates the role of formyl peptide receptor 2 (FPR2), a G protein-coupled receptor, in cisplatin-induced hearing loss. We demonstrate a significant upregulation of FPR2 in the cochlea of mice after cisplatin exposure, accompanied by profound hearing loss. Blocking FPR2 with either genetic (knockdown) or pharmacological (antagonist Boc-2, 50 µg/kg) strategies mitigates cisplatin-induced hearing impairment. Our in vivo experiments indicate that intraperitoneal injection of Boc-2 substantially alleviated the increase in auditory brainstem response (ABR) thresholds induced by cisplatin in mice. Mechanistically, FPR2 directly activates ERK1/2 and NF-κB signaling pathways, triggering a pro-inflammatory cytokine storm and subsequent hair cell apoptosis in the cochlea. Furthermore, FPR2 inhibition substantially attenuates cisplatin-induced inflammatory factor release and hair cell death. These findings identify FPR2 as a novel mediator of cisplatin-induced ototoxicity, suggesting its potential as a therapeutic target for preventing hearing loss in cancer patients.