This study investigates circulating proteins causally linked to erectile dysfunction (ED) using Mendelian randomization (MR) analysis, with a focus on metabolic mediation and drug discovery.

Large-scale two-sample MR and colocalization analyses were conducted using proteomics data (Olink and deCODE) as exposures and FinnGen data as outcomes. Mediation MR explored interactions between 1,400 blood metabolites and five identified proteins. Functional analyses included pathway enrichment, druggability assessments, and molecular docking.

Five proteins (AMN, ESM1, KIR2DL2, PIGR, TNFRSF6B) were identified and validated. Mediation MR revealed that 1-palmitoyl-2-linoleoyl-GPC promotes AMN expression, exacerbating ED, while N-formylmethionine and glycine-to-serine ratio reduce ED risk via ESM1. Stearoyl sphingomyelin enhances TNFRSF6B’s protective effect on ED. Drug-target analysis identified chlortetracycline (AMN), retinoic acid (ESM1), clopamide (KIR2DL2), and isoguanine (PIGR) as potential therapeutic candidates, with molecular docking confirming strong binding affinities.

This study clarifies protein-mediated mechanisms underlying ED and highlights novel therapeutic targets for clinical application.