Ginsenoside Rh1 inhibits tumor growth in mice with colorectal cancer and depressive symptoms via modulation of the gut microbiota and tumor microenvironment

Depression can accelerate the progression of colorectal cancer (CRC), and depressive remission improves cancer outcomes. Ginsenoside Rh1, the main metabolite of a steroidal saponin extracted from <i>Panax ginseng</i>, improves memory and learning and to inhibit tumor growth. However, its anticancer effects and mechanisms in CRC complicated by psychological stress remain unclear. The present study aimed to investigate the protective effect of Rh1 against CRC with coexisting symptoms of depression. A CRC xenograft mouse model exposed to chronic restraint stress (CRS) was established. Behavioral changes, 5‑hydroxytryptamine (5‑HT) levels, cytokine expression, intestinal microbiota diversity, T‑cell recruitment, myeloid‑derived suppressor cell (MDSC) proportions and dendritic cell (DC) maturation were analyzed following treatment of the mice with Rh1. Results showed that Rh1 inhibited tumor growth, ameliorated depressive‑like behaviors, enhanced cognitive function, upregulated brain 5‑HT and serum noradrenaline levels, and decreased serum cortisol, corticotropin‑releasing hormone, adrenaline, interleukin‑6, C‑X‑C motif chemokine ligand 1 and tumor necrosis factor‑α levels in mice with CRC under CRS. Furthermore, Rh1 intervention attenuated gut dysbiosis and decreased the Firmicutes/Bacteroidota ratio. Antibiotic‑induced depletion of gut bacteria further confirmed the involvement of gut microbiota in the anticancer and antidepressant effects of Rh1. Rh1 also promoted T cell activation and DC maturation, and reduced MDSC frequency, thereby reshaping the immune microenvironment. These findings indicate that Rh1 inhibited CRC tumor growth in the CRS‑exposed mice by stimulating the immune response and modulating the gut microbiota. Thus, it is suggested that Rh1 has potential as a novel therapeutic strategy for patients with CRC and depression.