Cochlear endoplasmic reticulum stress causes connexin 26 degradation is involved in age-related hearing loss

Age-related hearing loss (ARHL) represents a progressive auditory disorder. Growing evidence indicates that degradation of connexin 26 (Cx26) in cochlear may constitute one of the pathogenic mechanisms in ARHL. However, the molecular mechanisms underlying age-related Cx26 degradation remain unclear. We systematically analyzed Cx26 expression patterns in C57BL/6J mice across different age groups and confirmed an age-dependent downregulation of Cx26 in the mouse cochlea. Notably, we observed concurrent upregulation of endoplasmic reticulum (ER) stress markers Glucose-regulated protein 78 (GRP78) and protein disulfide isomerase (PDI) in aged cochlear tissues. Furthermore, <i>in vitro</i> experiments demonstrated that ER stress significantly reduced Cx26 protein levels in cochlear explants. Mechanistically, we observed enhanced expression of ubiquitination-related proteins Nedd4 and Eps15 with evident colocalization with Cx26 in an ER stress mouse model. In summary, our findings demonstrate that Cx26 ubiquitination mediated by cochlear ER stress is the main cause of Cx26 degradation in the cochlea of aged mice.