Yang Huiwen, Xie Yi, Yu Jintao, Shi Mengwen, Li Yutian, Cai Yifan, Cai Qinming, Huang Fang, Ye Zhewei, Wang Hui, Sun Yu
Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Intelligent Medical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Sci Rep. 2025 May 12;15(1):16474. doi: 10.1038/s41598-025-01509-x.
Tinnitus is a prevalent and distressing medical symptom, and no effective pharmacological treatment currently exists. Despite significant advances, tinnitus remains a scientific enigma. To explore the molecular underpinnings of tinnitus, we developed a noise-induced tinnitus model in mice and utilized metabolomics to identify key differences in metabolic pathways. Our results revealed that oxidative stress-related pathways, including glutathione (GSH) metabolism, were significantly enriched in the auditory cortex of mice exhibiting tinnitus-like behavior. To further explore the role of oxidative stress, we examined the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) in tinnitus by conducting experiments in Nrf2 knockout (Nrf2-KO) mice. While Nrf2-deficient mice did not develop spontaneous tinnitus or hearing loss, they displayed increased susceptibility to prolonged tinnitus-like behavior after noise exposure. This was accompanied by heightened microglial activation, neuroinflammation, and significant alterations in gut microbiota composition, including greater diversity and dysbiosis. Our findings highlight a novel mechanism underlying tinnitus, emphasizing the role of oxidative stress in the auditory cortex and its connection to noise-induced tinnitus. The deficiency of Nrf2 in mice increases their susceptibility to tinnitus, suggesting that Nrf2 may serve as a promising therapeutic target for preventing noise-induced tinnitus.
耳鸣是一种常见且令人痛苦的医学症状，目前尚无有效的药物治疗方法。尽管取得了重大进展，但耳鸣仍然是一个科学谜团。为了探索耳鸣的分子基础，我们在小鼠中建立了噪声诱导的耳鸣模型，并利用代谢组学来识别代谢途径中的关键差异。我们的结果显示，与氧化应激相关的途径，包括谷胱甘肽（GSH）代谢，在表现出类似耳鸣行为的小鼠听觉皮层中显著富集。为了进一步探索氧化应激的作用，我们通过在Nrf2基因敲除（Nrf2-KO）小鼠中进行实验，研究了核因子红细胞2相关因子2（Nrf2）在耳鸣中的作用。虽然Nrf2缺陷小鼠没有出现自发性耳鸣或听力损失，但在噪声暴露后，它们对长时间类似耳鸣行为的易感性增加。这伴随着小胶质细胞激活增强、神经炎症以及肠道微生物群组成的显著改变，包括多样性增加和生态失调。我们的研究结果突出了耳鸣潜在的一种新机制，强调了氧化应激在听觉皮层中的作用及其与噪声诱导耳鸣的联系。小鼠中Nrf2的缺乏增加了它们对耳鸣的易感性，这表明Nrf2可能是预防噪声诱导耳鸣的一个有前景的治疗靶点。
