Long-term artificial sweetener exposure increases the risk of atherosclerosis

This study aimed to elucidate the potential molecular mechanisms by which artificial sweeteners contribute to the initiation and progression of atherosclerosis, with the goal of providing a theoretical basis for the safety evaluation of artificial sweeteners and the prevention and treatment of atherosclerosis. Targets associated with seven artificial sweeteners (aspartame, acesulfame, sucralose, NHDC, cyclamate, neotame, and saccharin) were retrieved from the CTD and ChEMBL databases. Additional target screening was performed using SwissTargetPrediction, SEA, TargetNet, and PharmMapper. Disease Ontology (DO) enrichment analysis was conducted to identify diseases potentially linked to artificial sweetener targets. Atherosclerosis-related targets were obtained from GeneCards, DisGeNET, and TTD databases, and their union was taken. Weighted gene coexpression network analysis (WGCNA) was applied to identify key modules associated with immune cell infiltration. Mendelian randomization (MR) was performed to identify core targets with potential causal effects. Single-sample GSEA and CellChat analyses were conducted for core targets. Finally, molecular docking and molecular dynamics simulations were used to evaluate the binding stability between core target proteins and artificial sweeteners. A total of 795 targets associated with the seven artificial sweeteners were identified. DO enrichment analysis revealed significant associations with atherosclerosis. Integration of targets from GeneCards, DisGeNET, and TTD yielded 2904 atherosclerosis-related targets. Intersection with 572 DEGs from GEO datasets identified 53 overlapping targets. Further intersection with WGCNA key module genes yielded 13 potential candidate targets. MR analysis indicated strong causal associations of SCARB1 and ST14 with atherosclerosis. Molecular docking and dynamics simulations confirmed stable binding between SCARB1/ST14 proteins and artificial sweeteners. Artificial sweeteners may promote the development and progression of atherosclerosis by modulating cholesterol metabolism via the SCARB1 target and influencing macrophage migration through the ST14 target.