Inhibiting Ferroptosis in Type I Hair Cells of the Utricle Might Be a Promising Strategy for Treating Cisplatin-Induced Vestibulotoxicity.

Abstract

Cisplatin-induced peripheral vestibular toxicity can significantly affect the quality of life of cancer patients undergoing treatment. In this study, we established a model of cisplatin-induced vestibulotoxicity that demonstrated significant vestibular dysfunction, closely mirroring the condition of cancer patients receiving cisplatin treatment. Following cisplatin administration, Type I and Type II vestibular hair cells (vHCs) exhibited progressive loss, with Type I vHCs showing greater susceptibility to the drug. In vestibular tissues treated with cisplatin, evidence was found for the induction of ferroptosis, as indicated by alterations in several key ferroptosis regulator genes and the activation of ferroptosis biomarkers. Furthermore, these phenotypes were ameliorated by the administration of Fer-1. In Atoh1-Gpx4-/- mice vHCs, increases in reactive oxygen species (ROS) and Fe2+, along with reductions in mitochondrial cristae, cell membrane rupture, and cytoplasmic vacuolation, suggest the activation of ferroptosis. Notebly, the phenotypes observed in Atoh1-Gpx4-/- mice closely resembled those induced by cisplatin in the utricle. Our findings also demonstrated that the FDA-approved madecassic acid effectively mitigates vHC loss resulting from Gpx4 ablation and cisplatin administration through the modulation of Acsl3 and Gpx4. In summary, inhibiting ferroptosis may represent a potential strategy to protect against vestibular dysfunction caused by cisplatin-induced vestibulotoxicity.