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Targeting the SMG9–Wnt/β-catenin axis: A novel mechanism by which ginsenoside Rh2 suppresses triple-negative breast cancer progression

Year: 2026

Type: article

Abstract: Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options, underscoring the need for new treatment approaches. Ginsenoside Rh2 (G-Rh2) has demonstrated antitumor effects across multiple cancer types; however, its effects and underlying molecular mechanisms in TNBC remain poorly understood. Methods: TNBC cell viability was measured using the CCK-8 assay.Flow cytometry was used to evaluate cell cycle distribution and cell apoptosis. Proteomic analysis was performed to identify potential downstream targets of G-Rh2. The functional roles of downstream targets were validated by western blotting, flow cytometry, and luciferase reporter assays. Molecular docking was conducted to characterize protein-ligand interactions at the atomic level. Results: G-Rh2 markedly decreased MDA-MB-468 and BT549 cells viability in a concentration-dependent manner, with IC50 values of 31.74 μM and 49.63 μM, respectively. G-Rh2 treatment induced G0/G1 phase arrest and enhanced cell apoptosis. Mechanistically, G-Rh2 suppressed the Wnt/β-catenin signaling pathway through SMG9 downregulation. Molecular docking demonstrated a stable interaction between G-Rh2 and SMG9, with a minimum binding energy of -3.4 kcal/mol, indicating direct molecular engagement. Conclusion: This study demonstrates that G-Rh2 exerts potent antitumor effects in TNBC by inducing cell cycle arrest and promoting cell apoptosis. Furthermore, G-Rh2 suppresses tumor progression by targeting the SMG9-Wnt/β-catenin axis. These findings identify SMG9 as a novel mediator of G-Rh2 activity, provide mechanistic insight into its antitumor effects, and highlight SMG9 as a promising therapeutic target for TNBC.

Source: Journal of Ginseng Research

DOI: 10.1016/j.jgr.2026.101112