Garcinone C Suppresses Cancer Stem Cells and Induces Apoptosis in Triple‐Negative Breast Cancer Through Canonical Wnt Signaling

ABSTRACT Natural phytochemicals derived from dietary sources have demonstrated promising anticancer potential with favorable safety profiles. Among them, Garcinone C (Gar. C), a xanthone derived from mangosteen ( Garcinia mangostana ), demonstrated superior antitumor activity compared to other derivatives in our preliminary screening. Here, we report the first comprehensive evaluation of the efficacy of Gar. C against triple‐negative breast cancer (TNBC) using both in vitro and in vivo models. Gar. C significantly inhibited cell viability and stemness in TNBC cell lines (SUM159 and SUM149) in a dose‐dependent manner, with IC 50 values of 4.54 ± 0.13 µM and 5.97 ± 0.16 µM, respectively. Mechanistically, Gar. C induced mitochondrial‐mediated apoptosis, as indicated by an increased Bax/Bcl‐2 ratio and loss of mitochondrial membrane potential, and triggered G 0 /G 1 cell cycle arrest via modulation of cyclin D1 and p21. Furthermore, Gar. C effectively suppressed cancer stemness, as evidenced by a reduced CD44 + /CD24 − population. RNA sequencing and Western blot analyses suggested that the inhibition of the Wnt/β‐catenin signaling pathway was a key mechanism contributing to its dual effects on inducing apoptosis and suppressing stemness. Importantly, in a xenograft mouse model using SUM159 cells, Gar. C significantly inhibited tumor growth and metastasis. These findings highlight the potential of Gar. C as a promising natural compound for the prevention and treatment of TNBC.