Dexmedetomidine antagonizes cisplatin-induced ototoxicity in Cochlear hair cells by alleviating endoplasmic reticulum stress via the PERK pathway.

Cisplatin (CIS) is a chemotherapy drug of significant importance frequently used in the treatment of solid tumors. However, irreversible sensorineural hearing loss limits the clinical application of CIS. Endoplasmic reticulum stress (ERS) is a cellular response mechanism to adverse stimuli, involving complex cellular activities that may play a crucial role in CIS ototoxicity. Dexmedetomidine (DEX) is a widely used sedative and analgesic agent with independent cytoprotective effects; however, its ability to protect cochlear hair cells from CIS-induced injury remains to be fully elucidated. Therefore, we aimed to develop experimental frameworks using the HEI-OC1 cellular model and cochlear samples, investigate how DEX protects against CIS-induced cytotoxicity, and elucidate the molecular pathways involved. Transcriptomic analysis of the CIS-induced damage model established in HEI-OC1 cells revealed that CIS significantly induced the expression of genes closely associated with ERS. Furthermore, CIS enhanced the expression of ERS-related proteins in HEI-OC1 cells, including caspase 12, BiP, and CHOP. The addition of DEX significantly reduced the morphological damage caused by CIS to hair cells in cochlear explants. Additionally, DEX enhanced the survival of HEI-OC1 cells under CIS treatment. Subsequent investigation revealed that DEX significantly suppressed the increase in p-PERK, p-eIF2α, and ATF4 proteins, induced by CIS, thereby effectively counteracting CIS ototoxicity. The use of PERK pathway agonists and inhibitors further corroborated the hypothesis that DEX alleviates ERS via the PERK pathway, thereby counteracting CIS ototoxicity. Collectively, DEX demonstrated considerable potential as a means of safeguarding hair cells in the cochlea against ototoxic effects induced by CIS.