Aspartame Increases the Risk of Pancreatic Ductal Adenocarcinoma

ABSTRACT Aspartame (APM) is a widely used artificial sweetener associated with various health concerns, including potential links to diabetes, cardiovascular diseases, and an increased risk of cancer. This study aims to investigate the association between APM and cancer risk. In total, 212 key genes were identified from the APM and pancreatic ductal adenocarcinoma (PDAC) targets, univariate Cox analysis across five cohorts, and single‐cell sequencing data of malignant cell populations. Twenty‐one significant targets were identified through the STRING database. Following machine learning analysis, eight significant targets were highlighted. GO analysis indicated that these core targets were involved in the positive regulation of fibroblast proliferation, stimulus‐specific miRNA transcription, and RNA polymerase II transcription repression. KEGG analysis suggested that the core targets were implicated in proteoglycans in cancer, the PI3K‐Akt signaling pathway, and microRNAs in cancer. Validation through HPA and immunoinfiltration analyses confirmed the relevance of the eight core targets. Ultimately, FN1, THBS1, and ITGB3 were identified as critical targets through pseudo‐time and cell‐cell interaction analyses, along with molecular docking and molecular dynamics simulation validation. This study demonstrates that APM consumption is associated with an increased risk of PDAC through FN1, THBS1, and ITGB3 targets, as revealed by integrative analysis.