Chen Junhao, Zhao Junxian, Zhang Zhi, Zhu Xingcheng, Zuo Jieming, Nie Zuqing, Fu Yuanzhi, Wang Haifeng, Tang Mengjun, Fu Shi
Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Department of Urology, 920th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Kunming, Yunnan, China.
Front Pharmacol. 2025 Jun 2;16:1568780. doi: 10.3389/fphar.2025.1568780. eCollection 2025.
This study aims to identify circulating proteins causally associated with erectile dysfunction (ED) using Mendelian randomization (MR) analysis.
We utilized two of the largest multi-center proteomics databases as exposures and the FinnGen database as the outcome source. A large-scale two-sample MR analysis, including coloc colocalization analysis and SMR (Summary data-based Mendelian Randomization) analysis, was conducted to evaluate the reliability of proteomic effects on ED outcomes. Additionally, MR mediation analysis involving 1,400 blood metabolites was performed to investigate how these proteins mediate the effect of blood metabolites on ED. Finally, protein-protein interaction analysis, pathway enrichment analysis, druggability assessments, and molecular docking were employed to further elucidate the mechanisms of ED and identify potential therapeutic targets.
Eight circulating proteins (AMN, ESM1, KIR2DL2, PIGR, SPINT1, SPP1, TNFRSF6B, TMEM9) were identified as causally associated with ED based on two-sample MR and coloc colocalization criteria. Among these, five proteins (AMN, ESM1, KIR2DL2, PIGR, TNFRSF6B) satisfied SMR validation, while SPINT1, TMEM9, and SPP1 were excluded. Several of these proteins were found to mediate the relationship between metabolites and ED. These proteins are recognized as either druggable targets or existing drug targets, with molecular docking results demonstrating favorable interactions with various drug candidates.
Using MR analysis, we identified five proteins associated with ED, clarified protein-mediated mechanisms, and proposed promising therapeutic targets for ED.
本研究旨在通过孟德尔随机化（MR）分析确定与勃起功能障碍（ED）存在因果关系的循环蛋白。
我们将两个最大的多中心蛋白质组学数据库作为暴露因素，将芬兰基因数据库作为结果来源。进行了大规模的两样本MR分析，包括共定位分析和基于汇总数据的孟德尔随机化（SMR）分析，以评估蛋白质组学效应与ED结果之间关系的可靠性。此外，还进行了涉及1400种血液代谢物的MR中介分析，以研究这些蛋白质如何介导血液代谢物对ED的影响。最后，采用蛋白质-蛋白质相互作用分析、通路富集分析、成药潜力评估和分子对接，进一步阐明ED的机制并确定潜在的治疗靶点。
根据两样本MR和共定位标准，鉴定出8种循环蛋白（AMN、ESM1、KIR2DL2、PIGR、SPINT1、SPP1、TNFRSF6B、TMEM9）与ED存在因果关系。其中，5种蛋白（AMN、ESM1、KIR2DL2、PIGR、TNFRSF6B）通过了SMR验证，而SPINT1、TMEM9和SPP1被排除。发现其中几种蛋白介导了代谢物与ED之间的关系。这些蛋白被认为是可成药靶点或现有药物靶点，分子对接结果表明它们与各种候选药物具有良好的相互作用。
通过MR分析，我们鉴定出5种与ED相关的蛋白，阐明了蛋白质介导的机制，并提出了有前景的ED治疗靶点。
