Pharmacological activation of GPX4 by selenomethionine attenuates cisplatin-induced ototoxicity and hearing loss.

Cisplatin, an extensively used and effective antineoplastic agent for treating various malignancies, is well known for its ototoxicity. However, clinical treatments for ototoxicity remain limited. In this study, we investigated the protective role of selenomethionine (SeMet), an organic selenium compound, against cisplatin-induced ototoxicity. Our results demonstrated that SeMet effectively elevated cell viability and alleviated hair cells (HCs) loss in cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants in vitro and partially restored cisplatin-induced hearing loss (CIHL) in C57BL/6J mice in vivo. Additionally, SeMet attenuated oxidative stress, mitochondrial damage and apoptosis in HCs. Network pharmacology analysis indicated that the effect of SeMet on CIHL was partially attributed to ferroptosis-related pathway. Subsequent experiments confirmed the prediction, showing that SeMet reduced lipid peroxidation and iron accumulation in HCs. Mechanistic studies further revealed that the protective effects of SeMet were mediated through the activation of glutathione peroxidase 4 (GPX4) rather than nuclear factor E2-related factor 2 (Nrf2). Inhibition of GPX4 using RSL3 or ML210 reversed the SeMet-induced reduction in ferroptosis and apoptosis, whereas inhibition of Nrf2 via siRNA or the inhibitor ML385 had no significant effect. Notably, SeMet did not compromise the ability of cisplatin to induce DNA damage and cell death in cancer cells. Collectively, these findings support SeMet as a promising protective agent for the prevention of CIHL and suggest that GPX4 may be a potential therapeutic target in managing CIHL.