Ginkgetin enhances the antitumor effect of Taxol on human breast cancer MCF-7 cells via ferroptosis mediated by the MDM2-p53-YAP1 axis.

Ginkgetin, a biflavone isolated from Ginkgo biloba, is a potent Wnt signaling inhibitor that can enhance the pharmacological effects of cisplatin on non-small cell lung cancer (NSCLC) by activating the ferroptosis pathway. However, few studies have examined the role of ginkgetin in regulating ferroptosis in breast cancer cells. In this study, ginkgetin was found to induce ferroptosis by increasing intracellular reactive oxygen species (ROS) accumulation through the downregulation of GPX4, SLC7A11, SLC40A1, and glutathione expression along with the upregulation of transferrin, glutamate, cystine, and cell-free ferroptosis markers. Ferroptotic activity was inhibited using ferrostatin-1, which interfered with ginkgetin-mediated regulation of ferroptosis-related factors, such as GPX4, SLC7A11, SLC40A1, and transferrin, and partially suppressed ginkgetin-induced activation of the ferroptosis pathway. Mechanistically, ginkgetin promoted p53 nuclear translocation and upregulated downstream YAP1 expression by inhibiting the suppressive effect of MDM2 on p53 in breast cancer cells, whereas ferrostatin-1 partially reversed these effects. Consequently, the pharmacological activity of Taxol in breast cancer cells was enhanced. Finally, using a cell line-derived xenograft (CDX) model, we found that ginkgetin induced ferroptosis and suppressed tumor growth, whereas the combined administration of Taxol and ginkgetin produced a synergistic antitumor effect in vivo. Overall, these findings indicate that ginkgetin enhances the tumor-suppressive effect of Taxol by activating ferroptosis through the MDM2-p53-YAP1 axis, suggesting a potential combination therapy for breast cancer treatment.