Mechanism exploration of di(2-ethylhexyl) phthalate (DEHP)-induced hepatocellular carcinoma.

Mechanism exploration of di(2-ethylhexyl) phthalate (DEHP)-induced hepatocellular carcinoma via network toxicology and molecular docking analysis.

T Wang, Yun-fen Zhou, Baoxue Ge, Dan-Dan Gong, P F Chen

Discov Oncol

Apr 23, 2026

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Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, and its development is closely associated with metabolic dysregulation. Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been implicated in hepatotoxicity and carcinogenesis; however, the molecular mechanisms linking DEHP exposure to HCC progression, particularly through metabolic reprogramming and immune microenvironment alterations, remain poorly understood. METHODS: In this study, we integrated two GEO HCC transcriptomic datasets and applied differential expression analysis and weighted gene co-expression network analysis (WGCNA) to identify DEHP-related gene modules. Potential DEHP targets were predicted using ChEMBL, PharmMapper, and SwissTargetPrediction. Functional enrichment and protein–protein interaction network analyses were performed, followed by hub gene identification using multiple machine learning algorithms, including LASSO, SVM-RFE, and Random Forest. Immune cell infiltration was evaluated using CIBERSORT, and molecular docking combined was conducted to validate DEHP–protein interactions. RESULTS: Integration of DEHP target predictions and HCC transcriptomic analyses identified 39 overlapping genes potentially associated with DEHP-related HCC. Functional enrichment analysis revealed significant involvement in xenobiotic metabolism, fatty acid degradation, PPAR signaling, and peroxisomal pathways. Network topology and machine learning approaches consistently highlighted ACACB, ADH4, and PCK1 as core hub genes, all of which showed significant differential expression between tumor and normal tissues and demonstrated strong diagnostic performance (AUC > 0.87). Immune deconvolution analysis revealed DEHP-associated immune landscape alterations, with hub gene expression exhibiting significant correlations with multiple immune cell subsets. Molecular docking indicated favorable binding between DEHP and the three hub proteins. CONCLUSIONS: This study provides systematic evidence that DEHP may contribute to HCC development through dysregulation of metabolic enzymes and remodeling of the immune microenvironment. ACACB, ADH4, and PCK1 may serve as potential biomarkers and mechanistic links between environmental DEHP exposure and hepatocarcinogenesis.