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

Abstract

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.