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This study investigated how mitophagy regulates ferroptosis in cisplatin\u2013induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL\/6J mouse model of cisplatin\u2013induced ototoxicity in vivo. Cisplatin suppressed the PTEN\u2013induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl\u2013CoA synthetase long\u2013chain 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\u2013induced hearing loss and blood\u2013labyrinth 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\u2013associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin\u2013induced ototoxicity.<\/jats:p>","DOI":"10.3390\/cells15181657","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:05:26Z","timestamp":1789391126000},"page":"1657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PINK1\u2013Associated Mitophagy Protects Against Cisplatin\u2013Induced Ototoxicity by Regulating the Subcellular Distribution of ACSL4"],"prefix":"10.3390","volume":"15","author":[{"given":"Ting","family":"Li","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2013Head and Neck Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"},{"name":"Institute of Otorhinolaryngology\u2013Head and Neck Surgery, Tongji Medical College, Huazhong University of Science 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