Targeting a master inflammatory switch in the aging cochlea attenuates sensory decline

Abstract Objective Age-related hearing loss (ARHL) is largely attributed to dysfunction of the cochlear stria vascularis (SV). This study aimed to define the molecular mechanisms underlying SV aging and identify therapeutic targets. Methods Lifespan transcriptomic profiling and systems-level analyses were performed on mouse cochleae to reveal age-associated pathways. Functional and pharmacological assays were used to examine the effects of IκB kinase (IKK) inhibition both in vitro and in aging mice. Results Aged SV displayed profound transcriptional reprogramming toward a pro-inflammatory and metabolically impaired state. A regulatory hub comprising AP-1, NF-κB, and CEBPB was identified as a master inflammatory switch. TNFα activation disrupted the blood-labyrinth barrier and mitochondrial function, while IKK inhibition reversed these effects and mitigated hearing loss in aging mice. Conclusions Targeting the IKK–NF-κB axis preserves cochlear integrity and offers a promising therapeutic strategy to prevent age-related hearing loss.