Li Wen, Li Yu, Wang Min, Liu Hao, Hong Guodong, Jiang Luhan, Liu Ziyi, Wu Yunhao, Yuan Liangjie, Zhao Xiaoxu, He Zuhong, Guo Siwei, Xiao Yu, Bi Xiuli, Xia Ming, Zou Guichang, Zhang Lining, Gao Jiangang, Fu Xiaolong
School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Mol Ther. 2025 Jul 2;33(7):3036-3055. doi: 10.1016/j.ymthe.2025.03.046. Epub 2025 Mar 30.
Age-related hearing loss (ARHL) is one of the most prevalent and complex disorders. Our previous study demonstrated that abnormal activation of mammalian target of rapamycin complex 1 (mTORC1) signaling in the cochlear neurosensory epithelium causes auditory hair cell (HC) damage and contributes to ARHL. However, the underlying mechanism of mTORC1 activation remains unclear. In this study, we identified tumor necrosis factor-alpha-induced protein 8-like 2 (TNFAIP8L2), an immune regulatory gene, as a potential candidate. To elucidate the effect of TNFAIP8L2 on mTORC1 signaling in the neurosensory epithelium and on hearing function, we generated a Tnfaip8l2-deficient (Tnfaip8l2) mouse model. We discovered that Tnfaip8l2 deficiency led to features of oxidative stress in cochlear HCs and age-related hearing degeneration, exhibiting a similar phenotype to the mTORC1-over-activated Tsc1-cKO mice described previously. Furthermore, rapamycin, a well-known mTORC1 inhibitor, significantly mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, we found that TNFAIP8L2 regulates mTORC1 signaling by simultaneously inhibiting the GTPase activity of Ras homolog enriched in brain (RHEB) and Ras-related C3 botulinum toxin substrate 1 (RAC1). Notably, both RHEB and RAC1 inhibitors alleviated the hearing phenotype observed in Tnfaip8l2 mice by inhibiting mTORC1 signaling. Collectively, our results provide insights into the activation of the mTORC1 pathway in aged mouse cochleae and positions TNFAIP8L2 as a valuable theoretical strategy.
年龄相关性听力损失（ARHL）是最常见且复杂的疾病之一。我们之前的研究表明，耳蜗神经感觉上皮中雷帕霉素复合物1（mTORC1）信号通路的异常激活会导致听觉毛细胞（HC）损伤，并促成ARHL。然而，mTORC1激活的潜在机制仍不清楚。在本研究中，我们确定了肿瘤坏死因子-α诱导蛋白8样2（TNFAIP8L2），一种免疫调节基因，作为一个潜在候选基因。为了阐明TNFAIP8L2对神经感觉上皮中mTORC1信号通路以及听力功能的影响，我们构建了Tnfaip8l2基因敲除（Tnfaip8l2）小鼠模型。我们发现Tnfaip8l2基因敲除导致耳蜗毛细胞出现氧化应激特征以及年龄相关性听力退化，表现出与之前描述的mTORC1过度激活的Tsc1条件性敲除小鼠相似的表型。此外，雷帕霉素，一种著名的mTORC1抑制剂，显著减轻了由Tnfaip8l2基因敲除引起的听力功能障碍。从机制上来说，我们发现TNFAIP8L2通过同时抑制富含脑的Ras同源物（RHEB）和Ras相关的C3肉毒杆菌毒素底物1（RAC1）的GTP酶活性来调节mTORC1信号通路。值得注意的是，RHEB和RAC1抑制剂都通过抑制mTORC1信号通路减轻了在Tnfaip8l2小鼠中观察到的听力表型。总的来说，我们的研究结果为老年小鼠耳蜗中mTORC1通路的激活提供了见解，并将TNFAIP8L2定位为一种有价值的理论策略。
