Phthalates unleashed: decoding ovarian carcinogenesis through multi-omics networks, single-cell insights, and molecular docking.

Background: Despite epidemiological studies linking phthalates to ovarian cancer, their multi-target molecular mechanisms remain unresolved, hindering biomarker discovery and preventive strategies. This study integrates network toxicology, multi-omics analyses, and molecular docking to systematically delineate phthalate-driven oncogenic pathways, thereby bridging mechanistic gaps and informing targeted interventions.

Results: We identified 234 potential targets related to phthalate exposure and ovarian cancer. Enrichment analysis revealed that these genes are associated with HIF-1 signaling, and metabolic pathways that promote cancer progression. Seven core genes were identified, with six (GAPDH, CASP3, PPARG, ESR1, CYCS, SIRT1, and CCND1) exhibiting differential expression in the TCGA ovarian cancer cohort. Single-cell analysis confirmed their widespread expression across various cell types, underscoring their roles in tumor biology. Molecular docking revealed specific binding interactions between phthalates and six core proteins.

Conclusions: Integrated computational analyses indicate that phthalates (DEP, DMP, DOP) may drive ovarian carcinogenesis through metabolic reprogramming (HIF-1α/glycolysis), strong binding to SIRT1/PPARα regulators, and tumor microenvironment remodeling. These findings establish a framework for prioritizing environmental carcinogens and identifying exposure biomarkers, with implications for reevaluating phthalate safety and elucidating the SIRT1-HIF1-PPARα axis in cancer pathogenesis.