Ginsenoside Rh2 inhibits epithelial-mesenchymal transition in triple-negative breast cancer cell via disrupting the HIF-1α/YAP nuclear translocation axis.

Ginsenoside Rh2 (G-Rh2) is a primary bioactive constituent of ginseng (Panax ginseng C.A. Meyer), has been demonstrated to possess anti-tumor potential. However, its specific inhibitory effects on triple-negative breast cancer (TNBC) and the associated molecular mechanisms have not been fully elucidated. The hypoxic microenvironment is a key factor driving TNBC malignancy and dissemination, often leading to enhanced tumor invasiveness and increased metastatic risk. This study aimed to evaluate the inhibitory effects of G-Rh2 on TNBC cells and tumor growth and to identify the key molecular mechanisms responsible. This study integrated multiple experimental techniques, including western blot, immunofluorescence, histopathological staining, co-immunoprecipitation, cellular thermal shift assay, cell scratch assay, and molecular docking. Additionally, network pharmacology, hypoxia inducible factor 1α (HIF-1α) overexpression validation, and HIF-1α small interfering RNA (si-RNA)-mediated knockdown were combined to systematically dissect its key regulatory pathways. G-Rh2 was shown to suppress the growth of breast tumors in mice and concurrently induce apoptosis in TNBC cells. The underlying mechanisms involved downregulation of HIF-1α expression, activation of the Hippo pathway to suppress cell migration and invasion, and intervention in the HIF-1α/YAP nuclear translocation axis, thereby inhibiting epithelial mesenchymal transition (EMT). This study systematically revealed the inhibitory effect of G-Rh2 on TNBC through in vivo and in vitro models, providing new mechanistic evidence and theoretical support for natural product-based antitumor research.