Assessing Genetic Risk of DKK3 and SLAMF6 in Erectile Dysfunction: A Comprehensive Analysis Based on Mendelian Randomization.

Erectile dysfunction (ED) is a multifactorial disorder that significantly impacts men's physical and mental health, as well as their interpersonal relationships, and traditional treatment options for this condition still face many challenges and limitations. This study aimed to identify key genetic factors associated with ED risk through Mendelian randomization analysis by integrating data from expression quantitative trait loci and protein quantitative trait loci across multiple cohorts. We also evaluated the roles of metabolic pathways using data from 1,400 plasma metabolites. Single-cell RNA sequencing (ScRNA-Seq) was used to analyze gene expression patterns of ED-related genes in various cell types, while molecular docking was employed to identify potential drug targets. Our findings indicate that DKK3 plays a protective role ( = 0.8555,  = .0087), while SLAMF6 is associated with increased ED risk ( = 1.2613,  = .0433). Metabolites such as piperine and choline phosphate mediate ED onset. ScRNA-Seq reveals reduced DKK3 expression in endothelial and smooth muscle cells and increased SLAMF6 expression in T cells, highlighting the roles of vascular homeostasis imbalance and immune dysregulation in ED pathogenesis. Molecular docking screens four small molecules, including icariin, luteolin, Danshenol A, and Danshenxinkun A as potential therapeutic agents. This study identified DKK3 and SLAMF6 as novel therapeutic targets for ED, provided a foundation for precision medicine based on vascular-immune regulation, and underscored the need for further mechanistic studies and clinical validation.