Aspartame may promote erectile dysfunction via DPP4-mediated endothelial dysfunction and apoptosis: evidence from network toxicology, molecular dynamics simulation, and experimental validation.
阿斯巴甜是使用最广泛的人工甜味剂之一，但其对男性生殖健康的潜在不良影响仍认识不足。本研究旨在探讨阿斯巴甜可能导致勃起功能障碍（ED）的潜在机制。采用SEA、SwissTargetPrediction和TargetNet识别阿斯巴甜的潜在靶点，同时从GeneCards收集ED相关基因。对重叠基因进行蛋白-蛋白相互作用、基因本体论和京都基因与基因组百科全书富集分析。使用GSE2457数据集识别差异表达基因，随后通过LASSO回归和列线图构建筛选关键靶点。进行分子动力学模拟以评估配体-蛋白结合的稳定性。随后使用阴茎海绵体内皮细胞进行划痕愈合和蛋白质印迹实验。共识别出阿斯巴甜与ED之间的133个重叠基因，主要富集于血管调节、内皮信号传导、细胞凋亡以及PI3K-Akt/HIF-1相关通路。对GSE2457的整合分析识别出7个重叠基因，其中DPP4、GLUL和HRAS被选为关键基因，DPP4显示出最强的预测价值。分子动力学模拟表明阿斯巴甜与DPP4之间结合稳定。阿斯巴甜损害内皮细胞迁移，增加DPP4和Bax表达，降低p-eNOS/eNOS和Bcl-2表达，而沙格列汀部分逆转了这些效应。阿斯巴甜可能通过诱导内皮功能障碍和细胞凋亡促进ED进展，DPP4有望成为潜在的关键靶点。
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). 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. 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. , 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. Aspartame may promote ED progression by inducing endothelial dysfunction and apoptosis, with DPP4 emerging as a potential key target.
Zhiqiang Dai, Shouqiang Wang, Zhigui Chen, Qiang Zhang, Boyi Wang. Aspartame may promote erectile dysfunction via DPP4-mediated endothelial dysfunction and apoptosis: evidence from network toxicology, molecular dynamics simulation, and experimental validation.. Frontiers in nutrition. 2026; doi:10.3389/fnut.2026.1841453.
Zhiqiang Dai, Shouqiang Wang, Zhigui Chen, Qiang Zhang, Boyi Wang (2026). Aspartame may promote erectile dysfunction via DPP4-mediated endothelial dysfunction and apoptosis: evidence from network toxicology, molecular dynamics simulation, and experimental validation.. Frontiers in nutrition. https://doi.org/10.3389/fnut.2026.1841453
Zhiqiang Dai, Shouqiang Wang, Zhigui Chen, Qiang Zhang, Boyi Wang. Aspartame may promote erectile dysfunction via DPP4-mediated endothelial dysfunction and apoptosis: evidence from network toxicology, molecular dynamics simulation, and experimental validation.[J]. Frontiers in nutrition, 2026 doi:10.3389/fnut.2026.1841453.
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