Transforming Growth Factor‐β‐Activated Protein 1 (<scp>TAK1</scp>) Regulates Necroptosis in Age‐Related Hearing Loss

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.