As a typical organophosphate flame retardant, 2-ethylhexyl diphenyl phosphate (EHDPP) is widely present in the environment through inhalation exposure, but its mechanism in promoting lung cancer progression remains unclear. This study integrates network toxicology, molecular docking, tumor bioinformatics analysis, and in vitro cell models to systematically investigate the molecular carcinogenic network of EHDPP. First, the potential toxicity of EHDPP was predicted using PROTox and ADMETlab toxicity prediction platforms. Multi-database integration and screening identified 355 potential targets associated with EHDPP-induced lung cancer. KEGG pathway and GO functional enrichment analyses revealed that these key genes were significantly enriched in positive regulation of cell migration, metabolic pathways, and the PI3K-AKT signaling pathway. Further analysis using STRING and Cytoscape software identified 20 core targets, including MAPK14, AKT1, RXRA, PTK2, PTPN11, and EGFR. By integrating core gene expression and prognostic data, four genes-EGFR, RAC1, RXRA, and HRAS-were identified as key molecular hubs potentially regulating EHDPP-driven malignant phenotypes in lung cancer. Analysis of publicly available scRNA-seq data revealed high expression of these four hub genes in immune-related cells as well as AT2 cells, suggesting their potential roles in lung cancer. Molecular docking confirmed moderate predicted binding affinity, suggesting potential interactions between EHDPP and core targets. Additionally, cell model experiments demonstrated that EHDPP significantly promotes the proliferation and migration of lung cancer cells via the PI3K-AKT signaling pathway. Mechanistically, EHDPP binds to EGFR and inhibits its ubiquitination-mediated degradation, thereby stabilizing EGFR protein and partly activating the downstream PI3K-AKT signaling pathway, which ultimately promotes lung cancer cell proliferation and migration. This study is the first to elucidate the molecular mechanism underlying the pro-carcinogenic effects of EHDPP at the interaction level, providing potential molecular marker clues and mechanistic basis for EHDPP-related environmental risk assessment.
Ding et al. (Sun,) studied this question.