Zhang Kun, Hou Bo, Yan Tao, Qiao Ruru, Qu Peng, Xu Xinbo, Zhang Hanbing
Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, China.
Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Exp Gerontol. 2025 Feb;200:112676. doi: 10.1016/j.exger.2025.112676. Epub 2025 Jan 10.
Age-related hearing loss (ARHL) is a common sensory disorder with significant public health implications. However, few effective treatment options are available. Mendelian randomization (MR) has been used to repurpose existing drugs and identify new therapeutic targets. Therefore, we performed a systematic genome-wide MR of drug-eligible individuals to explore potential therapeutic targets for ARHL.
We obtained data on the expression quantitative trait locis (eQTLs) of druggable genes, which were then subjected to two-sample MR analyses and co-localisation analyses with data from the ARHL genome-wide association study to identify genes highly associated with ARHL. Additionally, we conducted phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking to help develop more effective and targeted therapeutic treatments.
Overall, the MR analysis of eQTL data showed that 14 drug targets were significantly associated with ARHL. GO analysis of 14 potential targets revealed their primary involvement in biological processes such as the endoplasmic reticulum unfolded protein response, ER-nucleus signaling pathway, and fibroblast apoptotic process. Additionally, important cellular components include the Bcl-2 family of proteins and the endoplasmic reticulum lumen. After filtering using methods such as phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking, six potentially druggable genes (BAK1, AMFR, LAMP3, STK17B, ACP5, and CD9) and six drugs (beclomethasone, propyl pyrazole triol, momelotinib, monoisoamyl-2,3-dimercaptosuccinate, pterostilbene, and naftidrofuryl) that may affect ARHL outcomes were finally identified.
Our findings identified 14 potential drug targets for ARHL. These findings offer promising leads for more effective treatments for ARHL and help determine the priority of drug development, potentially reducing costs.
年龄相关性听力损失（ARHL）是一种常见的感觉障碍，具有重大的公共卫生意义。然而，有效的治疗选择很少。孟德尔随机化（MR）已被用于重新利用现有药物并确定新的治疗靶点。因此，我们对符合药物治疗条件的个体进行了全基因组范围的系统MR研究，以探索ARHL的潜在治疗靶点。
我们获取了可成药基因的表达数量性状位点（eQTLs）数据，然后将其与ARHL全基因组关联研究的数据进行两样本MR分析和共定位分析，以确定与ARHL高度相关的基因。此外，我们进行了全表型组研究、富集分析、蛋白质网络构建、药物预测和分子对接，以帮助开发更有效、更有针对性的治疗方法。
总体而言，eQTL数据的MR分析表明，14个药物靶点与ARHL显著相关。对14个潜在靶点的基因本体（GO）分析显示，它们主要参与内质网未折叠蛋白反应、内质网-细胞核信号通路和成纤维细胞凋亡过程等生物学过程。此外，重要的细胞成分包括Bcl-2蛋白家族和内质网腔。通过全表型组研究、富集分析、蛋白质网络构建、药物预测和分子对接等方法进行筛选后，最终确定了6个潜在的可成药基因（BAK1、AMFR、LAMP3、STK17B、ACP5和CD9）和6种可能影响ARHL结局的药物（倍氯米松、丙基吡唑三醇、莫美替尼、单异戊基-2,3-二巯基琥珀酸、紫檀芪和萘呋胺酯）。
我们的研究结果确定了14个ARHL的潜在药物靶点。这些发现为更有效地治疗ARHL提供了有希望的线索，并有助于确定药物开发的优先级，可能降低成本。
