Abstract This study aimed to elucidate mechanisms linking exposure to microplastic-associated phthalates—Di(2-ethylhexyl) phthalate (DEHP) and Dibutyl phthalate (DBP)—with colorectal cancer (CRC) pathogenesis. We integrated network toxicology and molecular docking to identify core molecular targets and pathways. Hub genes were identified through Protein–Protein Interaction (PPI) network analysis, their differential expression validated using TCGA data, and functional pathways explored via GO/KEGG enrichment. Binding affinities were assessed by molecular docking, and a cross-validation analysis against reference carcinogens was performed to validate the model. We identified 324 common targets, screening 13 differentially expressed hub genes in CRC. Functional enrichment linked these genes to oncogenic processes like PI3K-Akt signaling. Docking simulations revealed favorable binding affinities of DEHP and DBP with 8 key targets, including TP53, EGFR, and MAPK3. The strongest interactions were observed for DEHP with MMP9 (−7.8 kcal/moL) and DBP with both ESR1 and MMP9 (−7.0 kcal/moL). Cross-validation confirmed a core network of 6 hub genes shared with carcinogens Benzoapyrene (BaP) and Bisphenol A (BPA), validating the commonality of downstream pathways. This study proposes a validated molecular framework for phthalate-induced colorectal carcinogenesis, demonstrating that DEHP and DBP may promote CRC progression by targeting key proteins like MMP9 and ESR1. Crucially, our analysis reveals a novel “specificity + commonality” mechanism, identifying a common downstream oncogenic network while pinpointing a unique, ESR1-mediated pathway as a specific upstream trigger for phthalates. These findings offer novel mechanistic insights into the health risks of microplastic-associated pollutants.
Jiang et al. (Mon,) studied this question.