The potential role of the SIRT1‐Nrf2 signaling pathway in alleviating hidden hearing loss via antioxidant stress

Hidden hearing loss (HHL) is characterized by normal audiometric thresholds but impaired auditory function, particularly in noisy environments. In vivo, we employed auditory brainstem response (ABR) testing and ribbon synapses counting to assess changes in mouse hearing function, and observed the morphology of hair cells through scanning electron microscopy. SRT1720 was administered to the cochlea via round window injection. In vitro, western blot analysis and RT-qPCR were used, and Lenti-shNrf2 was used to knockdown Nrf2 expression. In addition, various oxidative stress indicators were detected by immunofluorescence, kit-based assays, and flow cytometry. ABR measurement of HHL mouse showed a significant increase in hearing threshold, as well as a decrease and delay in the I wave amplitude and latency on the first day after noise exposure. Histological observation showed a significant loss of ribbon synapses and stereocilia lodging. HHL mice exhibited oxidative stress, which was reduced by pretreatment with SRT1720. Additionally, SRT1720 could reduce hydrogen peroxide-induced oxidative stress in HEI-OC1 cells through activating the SIRT1/Nrf2 pathway. Subsequent experiments with Nrf2 knockdown confirmed the importance of this pathway. findings highlight oxidative stress as the primary contributor to HHL, with the SIRT1/Nrf2 signaling pathway emerging as a promising therapeutic target for alleviating HHL.