Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (5): 1483-1494.doi: 10.4103/NRR.NRR-D-24-00130

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Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Xihang Chen1, 2, 3, 4, 5, 6, # , Zhifeng Chen1, 2, 3, 4, 5, 7, # , Menghua Li 1, 2, 3, 4, 5, # , Weiwei Guo1, 2, 3, 4, 5, # , Shuolong Yuan1, 2, 3, 4, 5 , Liangwei Xu1, 2, 3, 4, 5 , Chang Lin6, * , Xi Shi 8, 9, * , Wei Chen1, 2, 3, 4, 5, * , Shiming Yang1, 2, 3, 4, 5, *   

  1. 1 Senior Department of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China;   2 State Key Laboratory of Hearing and Balance Science, Beijing, China;   3 Nattonal Clinical Research Center for Otolaryngologic Diseases, Beijing, China;   4 Key Laboratory of Hearing Science, Ministry of Educatton, Beijing, China;   5 Beijing Key Laboratory of Hearing Impairment Preventton and Treatment, Beijing, China;   6 Department of Otorhinolaryngology Head and Neck Surgery, The First Afffliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China;   7 Department of Otolaryngology Head and Neck Surgery, The 940th Hospital of Joint Logisttcs Support Force of Chinese PLA, Lanzhou, Gansu Province, China;   8 Key Laboratory of Tropical Biological Resources of Ministry of Educatton, School of Pharmaceuttcal Sciences, Hainan University, Haikou, Hainan Province, China;   9 Academician Workstatton of Hainan University, School of Pharmaceuttcal Sciences, Yazhou Bay, Sanya, Hainan Province, China
  • Online:2025-05-15 Published:2024-10-31
  • Contact: Shiming Yang, PhD, MD, shm_yang@163.com; Wei Chen, PhD, MD, chenwe301@sina.com; Xi Shi, PhD, 100002013036@xzhmu.edu.cn; Chang Lin, PhD, MD, linc301@sina.com.
  • Supported by:
    This work was supported by the Nattonal Key Research and Development Program of China, No. 2022YFC2402701 (to WC); Key Internattonal (Regional) Joint Research Program of the Nattonal Natural Science Foundatton of China, No. 81820108009 (to SY); the Nattonal Natural Science Foundatton of China, Nos. 81970890 (to WC) and 82371148 (to WG); Fujian Provincial Healthcare Young and Middle-aged Backbone Talent Training Project, No. 2023GGA035 (to XC); Spring City Plan, the High-level Talent Promotton and Training Project of Kunming, No. 2022SCP001 (to SY); the Natural Science Foundatton of Hainan Province of China, No. 824MS052 (to XS); and the Sixth Medical Center of Chinese PLA General Hospital Innovatton Culttvatton, No. CXPY202116 (to LX).

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Abstract:

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Key words:

4-hydroxynonenal, apoptosis, autophagy, cleaved caspase-3,  inflammation, NOD-like receptor family pyrin domain-containing 3 (NLRP3), noise-induced hearing loss, oxidative stress, Sestrin2, tranylcypromine