Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.

Age-related hearing loss (ARHL) is closely linked to mitochondrial dysfunction in cochlear hair cells; however, its molecular regulation remains unclear. Sestrin2 (SESN2), a stress-inducible protein crucial for regulating energy metabolism, has not been comprehensively studied in the context of ARHL. To investigate SESN2's role, cochlea-specific SESN2 overexpression and knockout mouse models were established via adeno-associated virus 9 (AAV9) delivery through posterior semicircular canal injection. These models, combined with an H2O2-induced accelerated-aging paradigm and H2O2-treated House Ear Institute-organ of Corti 1 (HEI-OC1) cellular oxidative injury system, were systematically evaluated using auditory brainstem response (ABR), immunofluorescence (IF), mitochondrial membrane potential assays, western blotting, and other methods. Analysis of ARHL mouse cochleae revealed downregulation of SESN2 in hair cells, accompanied by mitochondrial membrane disruption and increased apoptosis. In aged mice, SESN2 overexpression significantly improved low-frequency hearing thresholds (p < 0.01). Mechanistically, SESN2 reduced oxidative stress, restored mitochondrial function, and suppressed excessive PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy, thereby maintaining mitochondrial quality control. This study is the first to show that SESN2 protects against ARHL through a tripartite cascade: antioxidant defense, mitochondrial functional restoration, and dynamic mitophagy regulation. These findings highlight SESN2's pivotal role in auditory preservation and identify it as a promising new therapeutic target for age-related hearing deterioration.