Chrysin Synergistically Reverses Chemoresistance in Ovarian Cancer by Inhibiting Epithelial-Mesenchymal Transition

Background: Ovarian cancer (OC), a lethal gynecological malignancy, frequently develops resistance to cisplatin, which significantly contributes to chemotherapy failure. Chrysin, a natural flavonoid, has exhibited anti-tumor and chemosensitizing effects, but evidence specific to OC remains limited. Methods: Parental SKOV3 and CAOV3 cells were treated with chrysin alone to assess cell viability (cell counting kit-8 (CCK-8) and colony formation assays) and apoptosis (flow cytometry). The synergistic effects of chrysin combined with cisplatin were evaluated using CCK-8 assays and CompuSyn 1.0 software (ComboSyn, Inc., Paramus, NJ, USA). Subsequently, two cisplatin-resistant sublines (SKOV3/DDP and CAOV3/DDP) were generated by gradually increasing cisplatin exposure. Changes in epithelial-mesenchymal transition (EMT) protein levels between parental and resistant cells were compared using Western blotting, followed by repeated viability (CCK-8), colony formation, Transwell migration, and apoptosis (flow cytometry) assays in resistant lines. Transcriptome sequencing was performed to identify differentially expressed genes. Additionally, EMT-related proteins (E-cadherin, N-cadherin, vimentin, and Snail1) and components of the nuclear factor kappa B (NF-κB) pathway (p-P65, P105/P50, p-IKKα/β, and p-IκBα) were analyzed by Western blotting. A rescue experiment using the NF-κB activator phorbol 12-myristate 13-acetate (PMA) confirmed the involvement of the NF-κB pathway. Results: Chrysin inhibited proliferation, induced apoptosis, and synergistically enhanced the efficacy of cisplatin in both parental and cisplatin-resistant OC cells. Mechanistically, chrysin suppressed the NF-κB pathway, consequently reversing EMT associated with cisplatin resistance. Conclusions: Chrysin synergistically enhances cisplatin efficacy against OC, including cisplatin-resistant cells, by modulating the NF-κB/EMT pathway. These findings suggest that chrysin could serve as a promising strategy for overcoming cisplatin resistance and merit clinical investigation.