Potential disease-related risk of saccharin in ovarian cancer: An integrative multi-evidence analysis

Saccharin is a widely used artificial sweetener with controversial safety concerns, particularly regarding reproductive health. Using a network-toxicology framework, we integrated compound- and disease-target databases and intersected them with differentially expressed genes and WGCNA co-expression modules from GEO datasets, yielding 49 candidate targets. Protein-protein interaction analysis and functional prioritization identified five hubs: TNF, MMP2, ERBB2, BCL2L1, and NFE2L2. GO/KEGG enrichment indicated over-representation of biological processes related to inflammatory response, apoptosis, and oxidative stress, alongside multiple cancer-associated pathways. Molecular docking against representative target structures indicated favorable binding of saccharin across hubs, with binding energies ≤ -5.0 kcal/mol. Mendelian randomization then tested the causal effects of gene expression on ovarian cancer risk and suggested a protective signal for TNF (odds ratio [OR] 0.99886, P = 0.0448) and increased risk for BCL2L1 (OR 1.00128, P = 0.0188). In two independent GEO datasets (GSE26712 and GSE14407), TNF and BCL2L1 were identified as differentially expressed genes between tumor and normal tissues. Molecular dynamics simulations further supported binding stability, with backbone RMSD stabilizing at 0.16-0.19 nm. These findings offer mechanistic insights into saccharin-induced ovarian toxicity and support further evaluation of artificial sweeteners' reproductive risks.