Abstract
Aspartame, a widely used artificial sweetener, has been linked to various cancers, including kidney renal papillary cell carcinoma (KIRP). However, the molecular mechanisms underlying this association remain unclear. This study employed network toxicology and molecular docking to investigate potential mechanisms of aspartame-induced KIRP. Differentially expressed genes from TCGA were intersected with aspartame targets and KIRP-related genes, yielding 61 common targets. GO and KEGG analyses revealed enrichment in extracellular matrix degradation, signaling pathways, and immune microenvironment regulation. Univariate Cox regression identified 23 prognostically significant genes, from which multifactorial Cox regression with stepwise selection determined 8 core genes (APLNR, CYP2C19, EDNRA, KLK5, F2R, RAD51, AURKA, and TLR2). A risk model was constructed and validated through VIF analysis, Schoenfeld residual testing, and internal validation using a training-validation split. SHAP analysis identified EDNRA as the primary driver gene. Survival analysis demonstrated that the model effectively stratified KIRP patients, with risk score and tumor stage serving as independent prognostic factors. Molecular docking confirmed stable binding between aspartame and core target proteins. These findings provide mechanistic insights into aspartame-induced KIRP pathogenesis and establish a foundation for future experimental validation.