Wang Hanjing, Lv Yayun, Zhao He, Hao Zhihong, Zhai Xiaoyu, Wang Yan, Qiu Jingjing, Chen Liang, Zhou Jiamin, Cui Limei, Sun Yan
School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People's Republic of China.
Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People's Republic of China.
Aging Cell. 2025 Jun;24(6):e70013. doi: 10.1111/acel.70013. Epub 2025 Feb 28.
Inflammation plays an important role in age-related hearing loss (ARHL). Transforming growth factor-β-activated protein 1 (TAK1), a key factor upstream of inflammatory pathways, mediates various cell death pathways, potentially influencing the survival and death of cochlear hair cells. The DBA/2 J mouse model and the HEI-OC1 cell line were used to investigate the mechanism of TAK1-mediated inflammation in ARHL. Hematoxylin and eosin staining revealed significant histological damage in the cochlea of 16-week-old mice, along with an increase in auditory-evoked brainstem response thresholds. Concurrently, TAK1 mRNA levels decreased sharply, and necroptosis significantly increased in 16-week-old mice, indicating a correlation between TAK1 expression, necroptosis, and hearing loss. We subsequently constructed TAK1 knockdown and overexpression HEI-OC1 cells for further investigation. TAK1 knockdown in HEI-OC1 cells significantly activated the necroptotic pathway, characterized by an increase in necroptosis, along with up-regulation of RIPK3 and MLKL, and down-regulation of NF-κB and Caspase 8. However, TAK1 overexpression successfully prevented necroptosis in HEI-OC1 cells, leading to decreases in NF-κB, Caspase 8, RIPK3, and MLKL. We further treated TAK1 knockdown cells with necroptosis inhibitors and found that they could reverse the damage caused by TAK1 knockdown in HEI-OC1 cells. This preliminary study shows that TAK1-mediated necroptotic pathways play an important role in the pathogenesis of ARHL.
炎症在年龄相关性听力损失（ARHL）中起重要作用。转化生长因子-β激活蛋白1（TAK1）是炎症信号通路上游的关键因子，介导多种细胞死亡途径，可能影响耳蜗毛细胞的存活与死亡。本研究利用DBA/2 J小鼠模型和HEI-OC1细胞系，探讨TAK1介导的炎症反应在ARHL中的作用机制。苏木精-伊红染色显示，16周龄小鼠耳蜗出现明显的组织学损伤，同时听觉脑干反应阈值升高。与此同时，16周龄小鼠TAK1 mRNA水平急剧下降，坏死性凋亡显著增加，提示TAK1表达、坏死性凋亡与听力损失之间存在相关性。随后，我们构建了TAK1基因敲低和过表达的HEI-OC1细胞进行进一步研究。在HEI-OC1细胞中敲低TAK1可显著激活坏死性凋亡信号通路，表现为坏死性凋亡增加，RIPK3和MLKL上调，NF-κB和Caspase 8下调。然而，TAK1过表达成功抑制了HEI-OC1细胞的坏死性凋亡，导致NF-κB、Caspase 8、RIPK3和MLKL表达下降。我们进一步用坏死性凋亡抑制剂处理TAK1基因敲低的细胞，发现它们可以逆转TAK1基因敲低对HEI-OC1细胞造成的损伤。本初步研究表明，TAK1介导的坏死性凋亡信号通路在ARHL发病机制中起重要作用。
