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 primary cause of deafness in aging populations and lacks proven effective therapies. Protecting the survival and function of sensory outer hair cells (OHCs) represents a promising therapeutic strategy for AHL. Certain herbs have shown beneficial effects on OHCs, but a limited understanding of their mechanisms hinders their clinical application. This study aimed to investigate the underlying mechanism of curcumin analog C1 (C1), which has demonstrated a beneficial effect in treating AHL in aged C57BL/6 mice. Our results revealed that C1 delayed AHL progression and mitigated the loss of OHCs in both aged C57BL/6 mice and aging cultured sensory epithelium explants. Furthermore, C1 exhibited an antioxidative effect in the OHCs of AHL mice. Notably, the application of C1 reversed the inhibition of transcription factor EB (TFEB) nuclear translocation, which was accompanied by the restoration of autophagic capability in OHCs of aged mice. The knockdown of TFEB abolished the activating effect of C1 on autophagy and eliminated its antioxidative effect in aging hair cells, ultimately leading to hair cell damage. Consequently, our findings not only demonstrate the therapeutic potential of C1 for AHL but also provide deeper insights into the pathogenesis of this condition.