Curcumin analog C1 activates autophagy through a TFEB-dependent mechanism to protect sensory hair cells from oxidative stress in C57BL/6 mice with age-related hearing loss

Age-related hearing loss (AHL) is the leading cause of deafness in older adults, yet effective treatments remain unavailable. Preserving the viability and function of sensory outer hair cells (OHCs) offers a promising therapeutic approach for AHL. Although certain herbal compounds have demonstrated protective effects on OHCs, their clinical use is limited by an incomplete understanding of their mechanisms of action. This study sought to elucidate the mechanism underlying the effects of the curcumin analog C1 (C1), which has previously shown efficacy in mitigating AHL in aged C57BL/6 mice. Our findings indicate that C1 delays the progression of AHL and reduces OHC loss in both aged C57BL/6 mice and aging cultured sensory epithelium explants. Additionally, C1 exerts antioxidative effects within the OHCs of AHL mice. Importantly, treatment with C1 restored the nuclear translocation of transcription factor EB (TFEB), which was associated with the recovery of autophagic activity in OHCs of aged mice. Conversely, TFEB knockdown eliminated the ability of C1 to activate autophagy and abolished its antioxidative effects in aging hair cells, ultimately resulting in hair cell damage. Collectively, these results demonstrate the therapeutic potential of C1 for AHL while providing deeper insight into the disease’s underlying mechanisms.