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

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

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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.

4-hydroxynonenalapoptosisautophagycleaved caspase-3inflammationNOD-like receptor family pyrin domain-containing 3(NLRP3)noise-induced hearing lossoxidative stressSestrin2tranylcypromine

Xihang Chen、Zhifeng Chen、Menghua Li、Weiwei Guo、Shuolong Yuan、Liangwei Xu、Chang Lin、Xi Shi、Wei Chen、Shiming Yang

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Senior Department of Otolaryngology Head and Neck Surgery,Chinese PLA General Hospital,Chinese PLA Medical School,Beijing,China

State Key Laboratory of Hearing and Balance Science,Beijing,China

National Clinical Research Center for Otolaryngologic Diseases,Beijing,China

Key Laboratory of Hearing Science,Ministry of Education,Beijing,China

Beijing Key Laboratory of Hearing Impairment Prevention and Treatment,Beijing,China

Department of Otorhinolaryngology Head and Neck Surgery,The First Affiliated Hospital o

Department of Otolaryngology Head and Neck Surgery,The 940th Hospital of Joint Logistic

Department of Otorhinolaryngology Head and Neck Surgery,The First Affiliated Hospital of Fujian Medical University,Fuzhou,Fujian Province,China

Key Laboratory of Tropical Biological Resources of Ministry of Education,School of Pharmaceutical Sciences,Hainan University,Haikou,Hainan Province,China

Academician Workstation of Hainan University,School of Pharmaceutical Sciences,Yazhou Bay,Sanya,Hainan Province,China

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2025

10.4103/NRR.NRR-D-24-00130

中国神经再生研究(英文版)
中国康复医学会

中国神经再生研究(英文版)

影响因子：0.902
ISSN：1673-5374
年,卷(期)：2025.20(5)