Activating GPR55 protects cochlear hair cells against cisplatin-induced ototoxicity via inhibiting MAPK pathway

Cisplatin (CDDP) is an effective chemotherapeutic agent used to treat solid tumors, but it can cause irreversible hearing loss. Currently, there are no specific preventive measures available for this side effect. G protein-coupled receptor 55 (GPR55) exhibits antioxidant, anti-inflammatory, and anti-apoptotic properties and is implicated in various disease processes. Nevertheless, whether GPR55 plays a role in CDDP-induced hearing loss remains unclear. We explored the effects and mechanisms of O-1602, a GPR55 agonist, on CDDP-induced ototoxicity. Our results showed that GPR55 is present in cochlear hair cells and HEI-OC1 cells, with increased expression following CDDP exposure. Moreover, O-1602-induced activation of GPR55 markedly mitigated the ototoxic effects of CDDP in HEI-OC1 cells, cochlear explants, and mouse models by preventing oxidative stress and apoptosis. In addition, GPR55 protected against CDDP-induced damage via inhibiting the MAPK pathway. Therefore, GPR55 is a potential therapeutic target for preventing CDDP-induced ototoxicity.