Aspartame and cardiovascular disease: Unraveling potential molecular mechanisms through integrative network...

Aspartame, a widely used artificial sweetener, has raised growing concerns regarding its potential cardiovascular toxicity. While regulatory agencies deem it safe within established limits, emerging evidence suggests possible adverse effects on vascular and inflammatory systems. This study aimed to investigate the potential molecular mechanisms by which aspartame may contribute to cardiovascular disease, utilizing a network toxicology approach combined with molecular docking and dynamics simulation. Potential aspartame targets were predicted using ProTox 3.0 and ADMETlab 2.0 platforms, alongside ChEMBL, STITCH, and Swiss Target Prediction databases. Cardiovascular-related targets were identified via GeneCards, Online Mendelian Inheritance in Man, and the Therapeutic Target Database. Overlapping genes were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. A protein-protein interaction network was constructed and analyzed for hub gene identification. Molecular docking and 100 ns molecular dynamics simulations were performed to validate binding stability between aspartame and key targets. Fifty-three overlapping genes were identified between aspartame and cardiovascular disease-related targets. Three hub proteins - interleukin-1β, caspase-3, and SRC - were revealed as potential regulators of aspartame-induced cardiovascular effects. Aspartame demonstrated stable binding to these proteins, particularly CASP3. Functional enrichment highlighted the AGE-RAGE, NF-κB, and PI3K-Akt signaling pathways as key mediators. Our findings suggest that aspartame may influence cardiovascular health through coordinated modulation of inflammatory and apoptotic pathways. These results provide a molecular framework for further experimental validation and risk stratification in sensitive populations.