Ginsenoside Rg3 overcomes tamoxifen resistance through inhibiting glycolysis in breast cancer cells

Abstract Tamoxifen (TAM) resistance poses a significant clinical challenge in human breast cancer and exhibits high heterogeneity among different patients. Rg3, an original ginsenoside known to inhibit tumor growth, has shown potential for enhancing TAM sensitivity in breast cancer cells. However, the specific role and underlying mechanisms of Rg3 in this context remain unclear. Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM‐resistant MCF‐7/TamR and T‐47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF‐7/TamR and T‐47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF‐7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM‐resistant MCF‐7 cell proliferation in an in vivo model. In conclusion, this study highlights the contribution of Rg3 in enhancing the therapeutic efficacy of TAM in breast cancer, and suggests that targeting TAM‐resistant PFKFB3 overexpression may represent a promising strategy to improve the response to combination therapy in breast cancer.