Age-related hearing loss (ARHL) represents the most common sensory disorder among the elderly population. Degeneration of spiral ganglion neurons (SGNs) is a key pathological feature of ARHL; however, the underlying mechanisms remain inadequately elucidated. Glutathione peroxidase 3 (GPX3), a vital component of the body's antioxidant system, is integral to maintaining cellular redox homeostasis and promoting cell survival. Nevertheless, its involvement in the pathogenesis and progression of ARHL has not been sufficiently explored. Our study suggested that GPX3 expression in SGNs was significantly decreased, accompanied by increased oxidative stress and apoptosis with aging. Meanwhile, autophagy levels were downregulated in SGNs with increased age. Targeted upregulation of GPX3 in SGNs markedly reduced the hearing threshold, improved wave I amplitude, and alleviated oxidative stress and apoptosis in SGNs. Interestingly, overexpression of GPX3 also led to a significant upregulation in autophagy levels. However, the protective effect of GPX3 was reversed by the autophagy inhibitor. These findings were also confirmed in vitro experiments. Collectively, our results indicated that GPX3 could mitigate apoptosis and oxidative stress in SGNs by activating autophagy, thereby alleviating hearing loss in ARHL mice. Furthermore, we discovered that the small molecule drug ebselen could reduce degeneration and damage in SGNs and effectively enhance auditory function by activating autophagy in both in vivo and in vitro settings. These results offer novel targets and therapeutic strategies for the prevention and treatment of ARHL.
