Age-related hearing loss (ARHL), also referred to as presbycusis, is the leading cause of disabling hearing impairment, which has imposed a significant burden on social life and the global economy [1,2]. While the disorder is multifactorial, ARHL is critically associated with the dysfunction and loss of spiral ganglion neurons (SGNs) [3]. Within the cochlear nerve, SGNs serve as the primary neurons of the auditory system. Cochlear synapses facilitate the transmission of sound signals detected by the inner and outer hair cells to the SGNs, which then convey peripheral auditory information to the auditory center [4]. With advancing age, there is a progressive degeneration and loss of SGNs [5]. As SGNs are non-renewable, their loss and damage can result in irreversible impairment of auditory transmission within the cochlea, subsequently leading to a deterioration in speech recognition ability [6]. Notably, current research has observed an association between upregulated oxidative stress, abnormal autophagy, apoptosis, and SGN degeneration or loss [7]; however, whether and how these processes are causally linked, particularly in the context of aging, remains unclear.

High levels of reactive oxygen species (ROS), known as oxidative stress, have traditionally been linked to tissue damage and eventual cell death [8]. Recent studies have demonstrated alterations in the cochlear redox environment with age. Bermudez-Munoz et al. reported that an increase in NADPH production could effectively reduce cellular sensitivity to ROS and apoptosis in cochlear hair cells (HCs) [9]. Cuafrado et al. suggested that the transcription factor nuclear factor erythroid 2-related factor 2 could regulate the antioxidative response to ROS and maintain redox homeostasis by enhancing the expression of antioxidant proteins [10]. Drugs targeting ROS have been proposed as potential therapeutic strategies for ARHL, including various antioxidants such as vitamin C, glutathione, flavonoids, and N-acetyl-cysteine, which aim to mitigate the damage caused by excessive ROS [[11], [12], [13]]. However, the stringent limitations imposed by the blood-labyrinth barrier often result in insufficient drug concentrations in the inner ear following intravenous injection or oral intake [14]. Therefore, it is imperative to investigate the potential molecular mechanisms of oxidative stress within SGNs and identify novel therapeutic targets to prevent ARHL.

Autophagy is an essential dynamic mechanism for cellular defense and self-protection, facilitating the degradation of proteins and organelles in lysosomes to eliminate toxic and harmful substances within cells [15]. The dysfunction of autophagy with age adversely affects numerous cellular and molecular processes that drive aging (hallmarks of aging), including loss of proteostasis, inadequate stress responses, disrupted cellular energetics, persistent cellular senescence, and stem cell exhaustion, and so on [16]. An increasing body of evidence indicates that the downregulation of most autophagic processes with age supports the modulation of autophagy levels as a strategy to combat aging [17]. Also, adjusting autophagy levels can significantly influence the survival, death, and regeneration of HCs and SGNs [18]. However, research on autophagy within the auditory field remains limited. The modifications in autophagy levels in SGNs related to ARHL, along with their precise mechanisms, have yet to be conclusively demonstrated.

Glutathione peroxidase 3 (GPX3) is a crucial enzyme within the body's antioxidant defense system [19,20]. Moreover, it exhibits superior catalytic efficiency and substrate specificity relative to other family members. Beyond its antioxidant function, GPX3 also plays an essential role in regulating metabolic processes, cell proliferation, apoptosis, autophagy, and cell signaling pathways [21]. In numerous chronic systemic diseases, such as chronic kidney disease [22], chronic obstructive pulmonary disease [23], and cardiovascular diseases [24], the expression of GPX3 is considered diminished. In aging-related diseases, GPX3 activity progressively decreased with age, with a notable reduction observed in people aged 70 years and older [25]. However, the trend of GPX3 changing in ARHL is still undefined. Whether the changes are related to hearing and SGN damage, as well as the mechanism of action, is the main focus of our research.

In this study, we observed a downregulation of GPX3 expression in SGNs with advancing age. Further, the overexpression of GPX3 via gene therapy techniques could mitigate hearing loss and decrease SGN degeneration by activating autophagy. These findings reveal the critical role of GPX3 in elderly hearing loss and suggest its potential as a therapeutic target for the prevention of ARHL.