Mechanism of Colorectal Cancer Development under Exposure to Synthetic Phenolic Antioxidants Based on Network Toxicology and Molecular Docking

Background: Synthetic phenolic antioxidants (SPAs) find widespread application in a broad range of industries and everyday consumer products, posing potential health risks. However, the mechanisms linking SPAs to colorectal cancer (CRC) development remain unclear. We explored the underlying mechanisms and key targets of CRC under SPA exposure via network toxicology and molecular docking. Methods: Initially, we screened SPAs with carcinogenic risks, and identified potential targets from Swiss Target Prediction, SEA, Gene Cards, and TTD. Then a total of 222 common targets between SPAs and CRC were identified via Venn diagram analysis. We constructed a protein-protein interaction (PPI) network while hub genes were identified by Cytoscape software. GO and KEGG enrichment analysis were performed. We used RNA-seq data from the TCGA database to assess the expression differences and diagnostic values of hub genes. We finally conducted molecular docking analysis to analyze the interaction between the compounds and proteins. Results: The PPI network pinpointed hub genes such as SRC, MAPK1, HSP90AA1, EGFR, and ESR1. These genes are involved in PI3K-Akt, MAPK, TNF, and VEGF signaling pathways. Differential expression analysis revealed that ESR1, HSP90AA1, and HRAS were significantly overexpressed in CRC tissues with diagnostic potential. There is no doubt that AO245 had the strongest binding energy with AKT1 and SHC1 by molecular docking, suggesting they may be key targets for SPAs-mediated carcinogenesis. Conclusions： SPAs may promote CRC through multiple targets related to cell proliferation, inflammation, and oxidative stress. Hub genes like ESR1 could serve as potential biomarkers, and proteins like AKT1 and SHC1 could be intervention targets.