Toxicity and mechanistic analysis of di(2-ethylhexyl)phthalate in renal cell carcinoma progression: a systematic study with network toxicology and molecular docking strategies.

Abstract

Millions of tons of unrecycled plastic pollute landfills and oceans, and di(2-ethylhexyl) phthalate (DEHP), a plasticizer classified as a possible carcinogen, is found in many environments, and poses health risks. Renal cell carcinoma (RCC), one of the most prevalent malignancies, accounted for approximately 434,419 new cases and 155,702 deaths in 2022. DEHP can cause developmental dysregulation, reproductive impairments, tumorigenesis, and transgenerational diseases; however, the mechanisms underlying these effects remain unclear. This study aimed to elucidate the toxic targets and molecular mechanisms associated with DEHP exposure and RCC occurrence by integrating network toxicology and molecular docking, utilizing multilevel bioinformatics data. By systematically utilizing diverse databases, 82 targets associated with both DEHP and RCC were identified. Subsequent screening with STRING and Cytoscape revealed 25 key targets, including CASP3, BCL2, MMP9, BCL2L1, CTSS, and APP. GO and KEGG enrichment analyses revealed that these targets are involved in apoptosis, abnormal hormone activity, cancer-related signaling cascades, ligand-receptor interactions, and endocrine system signaling pathways. Molecular docking simulations via CB-Dock confirmed the high-affinity binding interactions between DEHP and these key targets. These results suggest that DEHP exposure may promote the development of RCC by regulating apoptosis and proliferation through pathways such as neuroactive ligand-receptor interactions, pathways related to cancer, and apoptosis. This study provides a theoretical basis for understanding the molecular mechanisms of DEHP-induced renal carcinogenesis and serves as a foundation for future experimental studies to validate these computational predictions regarding DEHP-associated tumor risk from plastic products and environmental exposure.