[The role of TXNIP-mediated ferroptosis in the senescence of cochlear hair cells in age-related hearing loss].

Objective: To investigate the role and molecular mechanism of Thioredoxin-interacting protein (TXNIP) in the pathogenesis of age-related hearing loss (ARHL), focusing on whether it mediates cochlear hair cell senescence by regulating the ferroptosis pathway, thereby providing new theoretical insights and potential therapeutic targets for the prevention and treatment of ARHL. Methods: 1-month-old and 15-month-old male C57BL/6 mice were selected to detect changes in TXNIP levels in their serum and cochlea. 5-month-old male C57BL/6 mice were used to establish a senescence model via intraperitoneal injection of D-galactose (D-gal), with intervention using the TXNIP-specific inhibitor SRI-37330. Auditory brainstem response (ABR) was employed to measure hearing threshold shifts; techniques including ELISA, immunohistochemistry, and Western blot were utilized to detect the expression of TXNIP and related molecules. In vitro, HEI-OC1 cells were cultured and a D-gal-induced senescence model was established. siRNA interference and inhibitor treatments were applied to assess cellular senescence, oxidative stress, ferroptosis, and other indicators. Results: Compared with 1-month-old mice, 15-month-old mice exhibited a significant increase in hearing thresholds and a marked upregulation of TXNIP expression in both serum and cochlear hair cells (P<0.01). D-gal induction led to significantly increased TXNIP expression in senescent HEI-OC1 cells. Inhibition of TXNIP expression notably improved cell survival rates and reduced β-galactosidase activity and reactive oxygen species (ROS) levels (P<0.05). In vivo experiments demonstrated that SRI-37330 intervention significantly delayed D-gal-induced hearing loss in mice and enhanced hair cell survival. Inhibition of TXNIP reduced intracellular iron accumulation and increased the levels of ferroptosis markers GPX4 and SLC7A11, indicating a decrease in intracellular ferroptosis. Conclusions: Upregulation of Txnip expression promotes ferroptosis in cochlear hair cells, thereby accelerating cellular aging. Conversely, inhibition of Txnip effectively delays aging, reduces ferroptosis, and consequently exerts a protective effect on hearing. Targeted intervention against TXNIP may represent a novel potential strategy for the prevention and treatment of age-related hearing loss.