Ginsenoside Rg5 inhibits colorectal cancer, at least partially by blocking the lysosomal degradation of colorectal cancer cells.

The development of novel low-toxicity, high-efficacy therapeutics for colorectal cancer is urgently needed, given its global burden of approximately two million new cases and one million deaths annually. In the present study, we demonstrated for the first time that Ginsenoside Rg5 (Rg5), a small-molecule compound isolated from red ginseng, significantly inhibited tumor growth of colorectal cancer in mouse models. In addition, the levels of autophagy-related proteins, including LC3-II and p62, were significantly increased in tumors from Rg5-treated mice. Further mechanistic investigations revealed that Rg5 suppresses lysosomal degradation in colorectal cancer cells through inhibition of ATP6V1A (a key subunit of V-ATPase), consequently blocking autophagic flux. This impairment of autophagy ultimately induces apoptosis in colorectal cancer cells and inhibits tumor progression. This study provides evidence that Rg5 functions as an autophagy inhibitor, laying the foundation for its application in colorectal cancer adjuvant therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-37091-z.