DEL-1 Attenuates Gentamycin-induced Ferroptosis and Apoptosis in Hair Cells Through AMPK/Autophagy-mediated Suppression of ER Stress

HYPOTHESIS: Developmental endothelial locus-1 (DEL-1), a myokine, has been shown to reduce endoplasmic reticulum (ER) stress in various experimental models. This study aimed to examine the impact of DEL-1 on gentamicin (GT)-induced ototoxicity in cultured hair cell-like cells. BACKGROUND: The long-term use of GTs for treating infections induces ER stress in the inner ear, leading to hair cell-like death and, as a result, hearing loss. METHODS: Protein expression was measured via Western blot analysis, and cell viability, caspase 3 activity, and iron levels were assessed. Apoptotic cells were identified via TUNEL staining. RESULTS: GT exposure triggered ferroptosis, apoptosis, and ER stress in HEI-OC1 cells, all of which were reversed by DEL-1 treatment. DEL-1 also promoted AMP-activated protein kinase (AMPK) phosphorylation and autophagy. Inhibition of AMPK with siRNA or 3-methyladenine (3-MA) reduced the protective effects of DEL-1 in the presence of GT. CONCLUSION: These findings suggest that DEL-1 mitigates ER stress via AMPK/autophagy signaling, reducing ferroptosis and apoptosis in GT-treated hair cell-like cells. These findings indicate that DEL-1, a muscle-secreted protein, may offer a therapeutic strategy for GT-induced hearing loss.