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

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.