From sweetener to risk factor: Network toxicology, molecular docking and molecular dynamics reveal the mechanism of aspartame in promoting coronary heart disease

Abstract

Aspartame, a widely used non-nutritive sweetener, has been epidemiologically linked to coronary heart disease (CHD), although the underlying mechanisms remain unclear. This study employed an integrative computational strategy combining network toxicology, molecular docking, and molecular dynamics to decode aspartame's CHD-promoting mechanisms. Initially, the toxicity profile of aspartame was predicted using ProTox 3.0 and ADMETlab 3.0, which highlighted significant cardiotoxicity. Through multi-source target screening of aspartame (PharmMapper, SEA, etc.) and CHD (GeneCards, OMIM), 216 shared targets were identified. Protein-protein interaction network analysis revealed 10 hub targets (INS, PPARGC1A, TNF, AKT1, IL6, MMP9, IGF1, PTGS2, SIRT1, PPARG). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed significant enrichment in lipid metabolism, inflammatory responses, insulin resistance, and atherosclerosis-related pathways. Molecular docking and molecular dynamics simulations (MDS) demonstrated high-affinity binding of aspartame to three core targets (PTGS2, TNF, and PPARGC1A), with a binding energy ≤ −7.0 kcal/mol, and confirmed high binding stability. This study reveals that aspartame may promote the pathogenesis of CHD by disrupting cardiovascular homeostasis through multi-target interactions, including inflammatory response, metabolic dysregulation, and vascular remodeling. These findings provide molecular evidence for re-evaluating the safety profile of aspartame and establish a computational framework to guide experimental validation and preventive strategies.