Qi Meihao, Gao Zejun, Qiu Yang, Wang Renfeng, Tian Keyong, Yue Bo, Zhang Xinyu, Zhang Peng, Wu Ziqi, Zhu Qingwen, Liu Zhenzhen, Ma Zhuoyao, Zhou Xueying, Han Yu, Chen Jun, Qiu Jianhua, Zha DingJun
Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
Department of Ophthalmology, Hainan Hospital, People's Liberation Army (PLA) General Hospital, Sanya, 572013, China.
Adv Sci (Weinh). 2025 Jun 26:e08830. doi: 10.1002/advs.202408830.
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.
大多数感音神经性听力损失（SNHL）患者最初可能会经历与耳蜗基底转外毛细胞（OHC）更高易损性相关的高频听力损失。然而，高频区域这种易感性的分子机制仍不清楚。在这里，通过单细胞RNA测序首次将NOX2鉴定为与顶转和基底转氧化损伤相关的差异表达基因。在新霉素和噪声损伤的小鼠耳蜗中，Nox2阳性OHC从蜗顶到蜗底逐渐增加，表明顶转和基底转OHC之间的NOX2表达明显存在显著差异。在NOX2基因敲除小鼠中，新霉素和噪声暴露引起的OHC损伤明显减少。此外,敲除NOX2可增加细胞质中Nrf2的表达以及OHC中Nrf2的核转位。此外，Nrf2抑制剂可抵消NOX2基因敲除对新霉素的保护作用。最后，当以Nox2为靶点时，人参皂苷Rg1被鉴定为一种对新霉素诱导的听力损失具有保护作用的化合物。总之，这些结果表明NOX2与耳蜗高频OHC易损性高度相关，是SNHL临床治疗的潜在干预靶点。
