An Investigation of the Toxicity and Mechanisms of Food Additives Based on Network Toxicology and GEO Databases: A Case Study of Aspartame

This study employs network toxicology, molecular docking, and molecular dynamics simulations to assess the characteristics and potential molecular mechanisms of aspartame-induced hepatocellular carcinoma (HCC). Utilizing ChEMBL, STITCH, and SwissTargetPrediction databases, potential target proteins associated with aspartame are identified. HCC-related targets are determined through bioinformatics and weighted gene co-expression network analysis (WGCNA). Gene enrichment analysis explores the signaling pathways related to aspartame-induced HCC. Further refinement using the STRING database and Cytoscape software highlights 15 key targets. Molecular docking, conducted using Autodock Vina, assesses the relationships between aspartame and each key target. Molecular dynamics simulations evaluate the binding capabilities of aspartame with core targets obtained through molecular docking. The results indicate that aspartame may induce HCC by modulating apoptosis and proliferation of liver cancer cells, affecting inflammatory signaling pathways, and regulating estrogen metabolism, posing to the occurrence and development of liver toxicity and associated inflammation, thereby leading to a risk of hepatocarcinogenesis. This study provides a theoretical foundation for understanding the molecular mechanisms underlying aspartame-induced HCC. Additionally, our network toxicology approach accelerates the elucidation of toxic pathways for uncharacterized food additives. Graphical Abstract