2. Academic Validation
  3. Transforming Growth Factor-β-Activated Protein 1 (TAK1) Regulates Necroptosis in Age-Related Hearing Loss

Transforming Growth Factor-β-Activated Protein 1 (TAK1) Regulates Necroptosis in Age-Related Hearing Loss

  • Aging Cell. 2025 Feb 28:e70013. doi: 10.1111/acel.70013.
Hanjing Wang 1 2 3 4 5,  Yayun Lv 2 3 4 5,  He Zhao 2 3 4 5,  Zhihong Hao 1 2 3 4 5,  Xiaoyu Zhai 2 3 4 5,  Yan Wang 2 3 4 5 6,  Jingjing Qiu 2 3 4 5,  Liang Chen 2 3 4 5,  Jiamin Zhou 2 3 4 5 6 7,  Limei Cui 2 3 4 5,  Yan Sun 2 3 4 5
Affiliations

Affiliations

  • 1 School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People's Republic of China.
  • 2 Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People's Republic of China.
  • 3 Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, Shandong, People's Republic of China.
  • 4 Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People's Republic of China.
  • 5 Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People's Republic of China.
  • 6 The Second School of Clinical Medicine of Binzhou Medical University, Yantai, Shandong, People's Republic of China.
  • 7 Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, People's Republic of China.
PMID: 40018883 DOI: 10.1111/acel.70013
Abstract

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.

Keywords

TAK1; age‐related hearing loss; inflammation; necroptosis; presbycusis.

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