Blood Metabolites as Mediators in Erectile Dysfunction: Insights from a Multi-Center Proteomics and Genetic Study

Junhao Chen¹Junxian Zhao²Zhi Zhang³Xingcheng Zhu⁴Jieming Zuo¹Zuqing Nie¹Yuanzhi Fu⁵Haifeng Wang^1*Mengjun Tang^6*Shi Fu^1*

• ¹The Second Affiliated Hospital of Kunming Medical University, Kunming, China
• ²Department of Urology, 920th Hospital of Joint Logistic Support Force, Kunming, Yunnan Province, China
• ³Yongzhou Central Hospital, Yongzhou, Hunan, China
• ⁴Qujing Second People’s Hospital, Qujing, Yunnan Province, China
• ⁵Kunming University of Science and Technology, Kunming, Yunnan Province, China
• ⁶No. 967 Hospital of PLA Joint Logistic Support Force, Dalian, Liaoning Province, China

Objective: 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.Results: Eight circulating proteins (AMN, ESM1, KIR2DL2, PIGR, SPINT1, SPP1, TNFRSF6B, TMEM9) were identified as causally associated with ED based on twosample 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.