Ginsenosides Rh2 and Rg3 in first-line combination therapy: Prospects for rapid clinical translation in drug-resistant triple-negative breast cancer.

Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), remains one of the most aggressive breast cancer subtypes, characterized by high metastatic potential, poor prognosis, and limited therapeutic options. Despite extensive clinical efforts, durable improvements in survival have been limited due to the intrinsic heterogeneity of TNBC and the rapid emergence of multidrug resistance (MDR), primarily mediated by P-glycoprotein (P-gp) overexpression. P-gp-enriched cancer stem cells frequently survive initial chemotherapy, repopulate tumors, and drive relapse. Therefore, effective first-line strategies capable of eliminating heterogeneous, drug-resistant populations are urgently needed. Ginsenosides derived from Panax ginseng have gained increasing attention as natural compounds with potent anticancer activity and excellent safety profiles. Among them, the panaxadiol-type ginsenosides Rg3 and Rh2 exhibit strong translational potential and are being actively explored as candidate adjuvant or first-line agents. Their multifaceted activities-anticancer efficacy in TNBC, inhibition of P-gp, MDR sensitization, cytoprotection of normal cells, compatibility with nanoparticle delivery systems, and availability of preclinical and clinical data-underscore their promise in overcoming resistance in TNBC. This review summarizes the evidence supporting Rg3 and Rh2 as multi-targeted agents capable of enhancing therapeutic efficacy and accelerating clinical application in drug-resistant TNBC.