Ding Shun, Tong Qiling, Liu Yixuan, Qin Mengyao, Sun Shan
ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
Institute of Microbiology, Heilongjiang Academy of Sciences, Harbin 150000, China.
Bioengineering (Basel). 2025 Jan 29;12(2):126. doi: 10.3390/bioengineering12020126.
Sensorineural hearing loss (SNHL) is a major contributor to hearing impairment, yet effective therapeutic options remain elusive. Mendelian randomization (MR) has proven valuable for drug repurposing and identifying new therapeutic targets. This study aims to pinpoint novel treatment targets for SNHL, exploring their pathophysiological roles and potential adverse effects. This research utilized the UKB-PPP database to access cis-protein quantitative trait locus (cis-pQTL) data, with SNHL data sourced from the FinnGen database as the endpoint for the MR causal analysis of drug targets. Colocalization analysis was employed to determine whether SNHL risk and protein expression share common SNPs. A phenotype-wide association analysis was conducted to assess the potential side effects of these targets. Drug prediction and molecular docking were subsequently used to evaluate the therapeutic potential of the identified targets. Four drug target proteins significantly associated with sensorineural hearing loss (SNHL) were determined by Mendelian randomization (MR) analysis and co-localization analysis. These drug targets include LATS1, TEF, LMNB2, and OGFR and were shown to have fewer potential side effects when acting on these target proteins by phenotype-wide association analysis. Genes associated with sensorineural hearing loss are primarily implicated in the Hippo signaling pathway, cell-cell adhesion, and various binding regulatory activities and are involved in the regulation of cell proliferation and apoptosis. Next, drugs for the treatment of SNHL were screened by the DsigDB database and molecular docking, and the top 10 drugs were selected based on -value. Among them, atrazine CTD 00005450 was identified as the most likely therapeutic target, followed by ampyrone HL60 DOWN and genistein CTD 00007324. In addition, LMNB2, LATS1, and OGFR could be intervened in by multiple drugs; however, fewer drugs intervened in TEF. This study has successfully identified four promising drug targets for SNHL, which are likely to be effective in clinical trials with minimal side effects. These findings could significantly streamline drug development for SNHL, potentially reducing the costs and time associated with pharmaceutical research and development.
感音神经性听力损失（SNHL）是听力障碍的主要原因，但有效的治疗方案仍然难以捉摸。孟德尔随机化（MR）已被证明在药物重新利用和确定新的治疗靶点方面具有价值。本研究旨在确定SNHL的新治疗靶点，探索其病理生理作用和潜在不良反应。本研究利用英国生物银行-公私合作项目（UKB-PPP）数据库获取顺式蛋白质定量性状位点（cis-pQTL）数据，以来自芬兰基因数据库的SNHL数据作为药物靶点MR因果分析的终点。采用共定位分析来确定SNHL风险和蛋白质表达是否共享常见的单核苷酸多态性（SNPs）。进行了全表型关联分析以评估这些靶点的潜在副作用。随后使用药物预测和分子对接来评估已确定靶点的治疗潜力。通过孟德尔随机化（MR）分析和共定位分析确定了四种与感音神经性听力损失（SNHL）显著相关的药物靶点蛋白。这些药物靶点包括大肿瘤抑制因子1（LATS1）、转录增强因子（TEF）、核纤层蛋白B2（LMNB2）和鸟苷酸环化酶激活受体（OGFR），并且通过全表型关联分析表明，作用于这些靶点蛋白时它们的潜在副作用较少。与感音神经性听力损失相关的基因主要涉及Hippo信号通路、细胞间粘附以及各种结合调节活动，并参与细胞增殖和凋亡的调控。接下来，通过药物信号数据库（DsigDB）和分子对接筛选治疗SNHL的药物，并根据P值选择前10种药物。其中，莠去津CTD 00005450被确定为最有可能的治疗靶点，其次是安乃近HL60下调和染料木黄酮CTD 00007324。此外，LMNB2、LATS1和OGFR可被多种药物干预；然而，干预TEF的药物较少。本研究成功确定了四个有前景的SNHL药物靶点，它们在临床试验中可能有效且副作用最小。这些发现可能会显著简化SNHL的药物开发， potentially reducing the costs and time associated with pharmaceutical research and development.（最后一句英文原文重复，译文保持一致）
