METTL3通过m6A修饰NFKBIA抑制NF-κB介导的炎症反应从而减轻年龄相关性听力损失
METTL3 mitigates age-related hearing loss by inhibiting NF-κB-mediated inflammatory responses through the m6A modification of NFKBIA.
文献信息
| PMID | 42754648 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Jingqian Tan |
| 作者单位 | Department of Otorhinolaryngology Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong Province, P. R. China. |
| 期刊 | Journal of molecular medicine (Berlin, Germany) |
| SCI 分区 | Q1 |
| IF | 5.3 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
年龄相关性听力损失（ARHL）是老年人中常见且致残性的感觉缺陷，慢性炎症是其关键致病驱动因素。RNA甲基转移酶METTL3是N6-甲基腺苷（m6A）修饰的主要介导因子，已被牵涉于多种衰老相关疾病；然而，其在ARHL中的功能作用和机制仍不明确。ARHL模型通过使用12月龄C57BL/6小鼠以及用LPS和D-半乳糖处理HEI-OC1听觉细胞建立。听觉功能和耳蜗病理分别通过听性脑干反应（ABR）阈值和苏木精-伊红（H&E）染色评估。炎症细胞因子水平、基因和蛋白表达通过ELISA、qPCR、Western blotting和免疫荧光检测。METTL3在炎症中的分子机制通过m6A RNA甲基化定量试剂盒、RIP-qPCR分析和RNA稳定性实验研究。我们发现，在ARHL小鼠耳蜗中NFKBIA和METTL3均显著下调。在HEI-OC1细胞中，NFKBIA过表达抑制了NLRP3炎症小体和促炎性NF-κB/IL-6/STAT3轴。此外，METTL3过表达减轻了NF-κB介导的炎症，而NFKBIA敲低后该效应显著减弱。机制上，METTL3直接结合NFKBIA mRNA并通过m6A修饰增强其稳定性。关键的是，在ARHL小鼠中，METTL3过表达恢复了NFKBIA水平，改善了听力损失和耳蜗损伤，并抑制了NLRP3炎症小体和NF-κB/IL-6/STAT3通路的激活。总之，METTL3通过增强NFKBIA的m6A修饰下调NF-κB/IL-6/STAT3/NLRP3介导的炎症反应，从而减轻ARHL。
英文摘要
Age-related hearing loss (ARHL) is a prevalent and debilitating sensory deficit in the elderly, with chronic inflammation being a key pathogenic driver. The RNA methyltransferase METTL3, a primary mediator of N6-methyladenosine (m6A) modification, has been implicated in various aging-related diseases; however, its functional role and mechanism in ARHL remain poorly defined. ARHL models were established using 12-month-old C57BL/6 mice and by treating HEI-OC1 auditory cells with LPS and D-galactose. Auditory function and cochlear pathology were assessed through auditory brainstem response (ABR) thresholds and hematoxylin-eosin (H&E) staining, respectively. Inflammatory cytokine levels, gene and protein expression, were measured using ELISA, qPCR, Western blotting, and immunofluorescence. The molecular mechanism of METTL3 in inflammation was investigated using m6A RNA methylation quantification kit, RIP-qPCR analysis, and RNA stability assay. We found that both NFKBIA and METTL3 were significantly downregulated in the cochleae of ARHL mice. In HEI-OC1 cells, overexpression of NFKBIA suppressed the NLRP3 inflammasome and the pro-inflammatory NF-κB/IL-6/STAT3 axis. Furthermore, METTL3 overexpression mitigated NF-κB-mediated inflammation, an effect that was significantly attenuated upon NFKBIA knockdown. Mechanistically, METTL3 directly bound to NFKBIA mRNA and enhanced its stability through m6A modification. Critically, in ARHL mice, METTL3 overexpression restored NFKBIA levels, ameliorated hearing loss and cochlear damage, and suppressed the activation of the NLRP3 inflammasome and the NF-κB/IL-6/STAT3 pathway. Collectively, METTL3 mitigated ARHL by downregulating the NF-κB/IL-6/STAT3/NLRP3-mediated inflammatory responses through the enhancement of NFKBIA m6A modification.