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

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

机构地区：[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]National Clinical Research Center for Otolaryngologic Diseases,Beijing,China [4]Key Laboratory of Hearing Science,Ministry of Education,Beijing,China [5]Beijing Key Laboratory of Hearing Impairment Prevention and Treatment,Beijing,China [6]Department of Otorhinolaryngology Head and Neck Surgery,The First Affiliated Hospital of Fujian Medical University,Fuzhou,Fujian Province,China [7]Department of Otolaryngology Head and Neck Surgery,The 940th Hospital of Joint Logistics Support Force of Chinese PLA,Lanzhou,Gansu Province,China [8]Key Laboratory of Tropical Biological Resources of Ministry of Education,School of Pharmaceutical Sciences,Hainan University,Haikou,Hainan Province,China [9]Academician Workstation of Hainan University,School of Pharmaceutical Sciences,Yazhou Bay,Sanya,Hainan Province,China

出　　处：《Neural Regeneration Research》2025年第5期1483-1494,共12页中国神经再生研究（英文版）

基　　金：supported by the National Key Research and Development Program of China,No.2022YFC2402701(to WC);Key International(Regional)Joint Research Program of the National Natural Science Foundation of China,No.81820108009(to SY);the National Natural Science Foundation 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 Promotion and Training Project of Kunming,No.2022SCP001(to SY);the Natural Science Foundation of Hainan Province of China,No.824MS052(to XS);the Sixth Medical Center of Chinese PLA General Hospital Innovation Cultivation,No.CXPY202116(to LX)。

摘　　要：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 d B 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 k Hz 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 domaincontaining 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

关 键 词：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 

分 类 号：R764.433[医药卫生—耳鼻咽喉科]