PINK1-Associated Mitophagy Protects Against Cisplatin-Induced Ototoxicity by Regulating the Subcellular Distribution of ACSL4.

Cisplatin-induced ototoxicity is a significant clinical issue linked to ferroptosis and mitophagy dysfunction. This study investigated how mitophagy regulates ferroptosis in cisplatin-induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL/6J mouse model of cisplatin-induced ototoxicity in vivo. Cisplatin suppressed the PTEN-induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl-CoA synthetase long-chain family member 4 (ACSL4), and decreased glutathione peroxidase 4. Pharmacological activation of mitophagy or PINK1 overexpression alleviated ferroptosis in vitro, while deferoxamine treatment reduced cisplatin-induced hearing loss and blood-labyrinth barrier damage in vivo. Mechanistically, restoration of mitophagy was associated with increased mitochondrial targeting and reduced cytosolic accumulation of ACSL4, potentially through mitophagic clearance, thereby suppressing ferroptosis. These findings support a model in which impaired PINK1-associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin-induced ototoxicity.