Aspartame may promote erectile dysfunction via DPP4-mediated endothelial dysfunction and apoptosis: evidence from network toxicology, molecular dynamics simulation, and experimental validation

Background Aspartame is one of the most widely used artificial sweeteners, but its potential adverse effects on male reproductive health remain insufficiently understood. This study aimed to investigate the potential mechanisms by which aspartame may contribute to Erectile dysfunction (ED). Methods Potential targets of aspartame were identified using SEA, SwissTargetPrediction, and TargetNet, while ED-related genes were collected from GeneCards. Overlapping genes were analyzed using protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The GSE2457 dataset was used to identify differentially expressed genes, followed by LASSO regression and nomogram construction to screen key targets. Molecular dynamics simulation was performed to evaluate the stability of ligand–protein binding. Penile corpus cavernosum endothelial cells were then used for wound healing and western blot assays. Results A total of 133 overlapping genes between aspartame and ED were identified, mainly enriched in vascular regulation, endothelial signaling, apoptosis, and PI3K-Akt/HIF-1-related pathways. Integrated analysis of GSE2457 identified 7 overlapping genes, among which DPP4, GLUL, and HRAS were selected as key genes, with DPP4 showing the strongest predictive value. Molecular dynamics simulation indicated stable binding between aspartame and DPP4. In vitro , aspartame impaired endothelial cell migration, increased DPP4 and Bax expression, and decreased p-eNOS/eNOS and Bcl-2 expression, whereas saxagliptin partially reversed these effects. Conclusion Aspartame may promote ED progression by inducing endothelial dysfunction and apoptosis, with DPP4 emerging as a potential key target.