NOX2 Contributes to High-Frequency Outer Hair Cell Vulnerability in the Cochlea

Most patients with sensorineural hearing loss (SNHL) may initially experience high-frequency hearing loss linked to greater vulnerability of outer hair cells (OHCs) in the cochlear basal turn. However, the molecular mechanism underlying this susceptibility in the high-frequency region remains unclear. Here, NOX2 is first identified as a differentially expressed gene related to oxidative damage in the apical and basal turns through single-cell RNA sequencing. In mouse cochleae damaged by neomycin and noise, Nox2-positive OHCs increase progressively from the apex to base, indicating that NOX2 expression clearly differed significantly between the apical and basal OHCs. In NOX2 knockout mice, OHC damage caused by neomycin and noise exposure is significantly reduced. Furthermore, knocking out NOX2 increases the expression of Nrf2 in the cytoplasm and Nrf2 nuclear translocation in OHCs. In addition, Nrf2 inhibitors counteract the protective effect of NOX2 knockout against neomycin. Finally, when Nox2 is used as the target, ginsenoside Rg1 is identified as a compound with protective effects against neomycin-induced hearing loss. In summary, these results indicate NOX2 is highly correlated with high-frequency OHCs vulnerability in the cochlea and is a potential intervention target for the clinical treatment of SNHL.