A comprehensive analysis reveals the potential risks and molecular connections between aspartame and polycystic ovary syndrome.

The widespread use of aspartame has raised increasing health concerns, particularly regarding its potential endocrine-disrupting effects and a possible association with polycystic ovary syndrome (PCOS), a condition marked by endocrine and metabolic abnormalities. This study systematically investigated the molecular mechanisms by which aspartame may contribute to PCOS pathogenesis using a network toxicology approach. A total of 281 common targets between aspartame and PCOS were identified. Protein-protein interaction network analysis and five topological algorithms revealed 20 hub targets significantly enriched in pathways such as endocrine resistance, TNF signaling, and progesterone-mediated oocyte maturation. Eight of these targets showed significant differential expression in PCOS patients. Weighted gene co-expression network analysis (WGCNA) further demonstrated that several of these hub targets are embedded in co-expression modules positively associated with PCOS phenotypes. Transcription factor prediction indicated that these targets are primarily regulated by FOS and JUN. Molecular docking showed favorable binding affinities between aspartame and both transcription factors. Subsequent molecular dynamics simulations supported the dynamic stability of aspartame binding to FOS and JUN. These findings suggest that aspartame may contribute to PCOS by modulating FOS- and JUN-mediated transcriptional programs, thereby disrupting biological pathways related to endocrine regulation and inflammation. Collectively, this study reveals a potential mechanism by which aspartame mediates PCOS and offers novel insights for toxicological assessment of food additives.