Exploring novel drug targets for erectile dysfunction through plasma proteome with genome.

Background: Currently, the treatment and prevention of erectile dysfunction (ED) remain highly challenging. Aim: This study conducted a systematic druggable genome-wide Mendelian randomization (MR) analysis to identify potential therapeutic targets for ED. Methods: A proteome-wide MR approach was employed to investigate the causal effects of plasma proteins on ED. Subsequently, summary data-based MR (SMR) analysis was performed to identify potential drug targets for ED. Enrichment analysis and protein-protein interaction (PPI) networks revealed the functional characteristics and biological relevance of these potential therapeutic targets. Drug prediction and molecular docking studies were conducted to validate the pharmacological activity of these identified targets. Finally, a systematic MR analysis was conducted to assess upstream intervention factors, such as lifestyles and diseases, associated with these targets, providing insights for the prevention and treatment of ED. Outcomes: This study identified several potential therapeutic targets for ED. Results: Proteome-wide MR analysis revealed that 126 genetically predicted plasma proteins were causally associated with ED. SMR analysis indicated that TMEM9 was associated with an increased risk of ED, while MDH1, NQO1, QDPR, ARL4D, TAGLN2, and PPP1R14A were associated with a decreased risk of ED. These potential targets were primarily enriched in metabolic and redox-related biological processes. Molecular docking indicated that the predicted drugs had favorable binding affinities with the proteins, further confirming the pharmacological value of these targets. Finally, 6 plasma proteins (MDH1, NQO1, QDPR, ARL4D, TAGLN2, and TMEM9) could be modulated by lifestyle- and disease-related factors. Clinical Implications: This study provides new insights into the etiology and potential drug targets of ED and contributes to the development of more effective treatments for ED and reducing the cost of drug development. Strengths and Limitations: This is a systematic and extensive study exploring the causal relationship between plasma proteins and ED, which helps to provide a comprehensive perspective to understand the role of potential targets in ED. However, we did not conduct this study in different types of ED or different stages of ED progression. Conclusion: In summary, this study identified 7 plasma proteins causally associated with ED and provided new insights into the etiology and potential drug targets for ED.