2-Ethylhexyl diphenyl phosphate exposure is associated with poorer overall survival in advanced high-grade serous ovarian cancer: Integrated epidemiological and experimental evidence implicating the ITGB1-FAK-AKT axis.

BACKGROUND: Organophosphate esters (OPEs) are globally used flame retardants and plasticizers with widespread human exposure. Whether OPE exposure affects survival in advanced high-grade serous ovarian cancer (HGSOC) and the underlying mechanisms remains unclear. We aimed to identify prognosis-related OPEs and explore their biological actions. METHODS: We conducted a nested case-control study within the Ovarian Cancer Follow-Up Study, including 159 deceased and 159 matched surviving patients with advanced HGSOC. Associations between urinary OPEs and all-cause mortality were evaluated using conditional logistic regression models. Mixture effects were examined using quantile g-computation and Bayesian kernel machine regression. Network toxicology, molecular docking, molecular dynamics simulations, and in vitro and in vivo experiments were performed to explore mechanisms. RESULTS: Higher urinary levels of bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were significantly associated with higher odds of mortality, with highest-versus-lowest tertile odds ratios (ORs) of 1.88 (95% confidence interval [CI]: 1.02-3.45), 2.62 (95% CI: 1.33-5.16), and 2.36 (95% CI: 1.23-4.53), respectively. Mixture analyses identified EHDPP as the predominant contributor. Network toxicology analysis identified the AKT signaling pathway as a key mediator, with ITGB1 highlighted as a key upstream target. Molecular docking and molecular dynamics simulations supported a stable EHDPP-ITGB1 complex, and cellular thermal shift assay confirmed intracellular interaction. EHDPP promoted colony formation, migration, vasculogenic ability, and xenograft tumor growth, accompanied by ITGB1 upregulation and FAK-AKT activation. CONCLUSIONS: OPE exposure, particularly EHDPP, is associated with poorer survival in advanced HGSOC. EHDPP may promote ovarian cancer progression through the ITGB1-FAK-AKT signaling axis. These findings highlight the potential prognostic relevance of EHDPP exposure in HGSOC.