Network toxicology and mechanistic insights reveal the oxytocin receptor (OXTR) as a key mediator of aspartame-associated atrial remodeling.

Atrial fibrillation (AF) is a major arrhythmic disorder with incompletely understood environmental triggers. Aspartame, a widely used artificial sweetener, has been linked to cardiovascular dysfunction, yet its role in AF remains unclear. This study aimed to elucidate the mechanistic link between aspartame and AF via oxytocin receptor (OXTR) modulation. Using a network toxicology strategy, 287 putative aspartame targets were identified; Mendelian randomization analysis singled out OXTR as a potential causal factor in AF. Functional enrichment of OXTR-interacting proteins implicated hormone signaling, neuroactive ligand-receptor interaction, and electrophysiological regulation. Transcriptomic profiling revealed low overall cardiac expression of OXTR, with enrichment in ventricular cardiomyocytes and strong correlation with cardiomyocyte markers. Molecular docking and molecular dynamics simulations confirmed stable binding of aspartame to OXTR, exhibiting binding energy and hydrogen bonding comparable to the natural ligand. In AC16 human cardiomyocytes, low-dose aspartame upregulated OXTR. It also increased COL1A1 and IL-6 expression, while reducing CACNA1C expression. OXTR knockdown reversed these effects. Collectively, our multi-level evidence indicates that aspartame may promote atrial remodeling through OXTR-dependent pathways involving fibrosis, inflammation, and ion-channel remodeling. OXTR emerges as a novel therapeutic target for mitigating aspartame-associated AF.