Integrated network toxicology suggests potential mechanisms involving environmental flame retardant TDCPP in ovarian cancer progression via “liver-to-ovary crosstalk.”

The environmental flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is epidemiologically associated with several core risk factors for ovarian cancer (such as hormonal dysregulation and infertility); however, the molecular mechanisms linking these adverse health outcomes remain unclear. This knowledge gap limits the precision and specificity of risk assessment. This study aims to utilize bioinformatics methods to suggest potential molecular pathways through which TDCPP influences the development of ovarian cancer. We employed an integrative analysis strategy combining computational toxicology and multi-omics data. Molecular docking simulations were utilized to evaluate potential molecular binding. Statistical analyses involved differential expression analysis, miRNA target prediction, and pathway enrichment to identify key regulatory networks. Our analysis identified potential associations between TDCPP (and its metabolite BDCPP) and three key ovarian cancer genes related to prognosis: MMP3 (invasion), and CYP3A4 and CYP3A43 (chemotherapy resistance). Multi-omics analysis identified an miRNA signature (miR-3677/3135/4436 family) associated with gene co-regulation. Given the liver-enriched characteristics of these miRNAs, we proposed a novel “liver-to-ovary crosstalk” hypothesis model of distal tumor progression. In this model, TDCPP exposure may involve the release of exosomes carrying dysregulated miRNAs from hepatocytes, thereby potentially remotely regulating ovarian gene expression. Furthermore, molecular docking simulations suggested that TDCPP and BDCPP could theoretically interact with the protein domains of MMP3 and CYP3A4, providing atomic-level clues for potential molecular binding effects. Starting from epidemiological associations, this study provides bioinformatics evidence regarding potential molecular mechanisms linking TDCPP to ovarian cancer risk. The proposal of miRNA-related regulatory pathways and a “liver-to-ovary crosstalk” hypothesis model offers a new perspective for understanding the systemic toxicity of the environmental pollutant TDCPP. Importantly, these findings provide testable hypotheses for future experimental validation and offer molecular-level clues for interpreting difficult-to-explain clinical cases, highlighting their significant public health and scientific value. Not applicable. Identifies a potential molecular link between the environmental flame retardant TDCPP and key ovarian cancer-associated genes using integrative bioinformatics. Identifies a miRNA signature (miR-3677/3135/4436 family) that correlates with the co-regulation of genes associated with tumor invasion and chemoresistance following TDCPP exposure. A novel “liver-to-ovary crosstalk” hypothesis model is proposed, providing a specific perspective for understanding distal tumor progression initiated by hepatic signaling as a potential inter-organ communication process. Provides evidence supporting a potential mechanism by which TDCPP exposure may contribute to tumor progression (invasion and chemoresistance), providing a hypothesis for environmental risk in advanced ovarian cancer. Provides a new computational strategy for investigating systemic toxicity and inter-organ crosstalk in environmental health and oncology.