Bisphenol a is associated with ovarian cancer chemoresistance via ecmCAF-mediated stromal remodeling: an integrative multi-omics study

Background BPA is a ubiquitous endocrine disruptor linked to ovarian cancer, yet its effect on chemotherapy efficacy is unknown. CAFs drive drug resistance via microenvironment remodeling. We investigated whether BPA exposure is associated with chemoresistance via CAF-mediated stromal reprogramming. Methods We performed single-cell RNA sequencing on ovarian cancer samples across treatment-naive, post-chemotherapy, and recurrent states (n = 10). BPA target gene set activity was quantified across cell types using AUCell scoring. Fibroblasts were re-clustered to characterize CAF subtypes. BPA target genes were integrated from public databases, with core targets prioritized through protein-protein interaction networks and molecular docking. Machine learning models were built for chemoresistance prediction, and in vitro validation was performed; CellChat inferred intercellular communication dynamics. Results Fibroblasts exhibited the highest BPA-driven activity among all tumor cells. The extracellular matrix CAF (ecmCAF) subtype showed elevated BPA scores. Integration of BPA targets, ecmCAF markers, and recurrence signatures yielded hub genes, with molecular docking predicting favorable BPA binding to PTGS2 (−7.7), MMP2 (−7.6), and SERPINE1 (−7.5 kcal/mol). CellChat revealed heightened CAF-to-epithelial pro-EMT and CAF-to-immune suppressive signaling in the recurrent sample. In vitro validation further showed that BPA treatment increased ACTA2 and COL1A1 expression in CAFs and that conditioned medium from BPA-treated CAFs enhanced SKOV3 resistance to cisplatin. Conclusion The BPA-ecmCAF axis represents a novel mechanism linking environmental exposure to ovarian cancer chemoresistance through microenvironment remodeling. These findings identify ecmCAF effectors as candidate exposure biomarkers and suggest that environmental risk assessment should consider the potential of BPA to compromise cancer treatment outcomes.