From licorice to the lab: Lanzhou University engineers a licorice-root compound into a promising two-pronged weapon against colorectal cancer

Colorectal cancer is one of the most common malignancies worldwide, with both incidence and mortality rising year by year. While chemotherapy remains a mainstay of treatment, most clinically used drugs cause significant side effects and show poor tissue selectivity, damaging normal cells alongside cancerous ones. Moreover, colorectal cancer is increasingly recognized as a highly immune-related disease: the tumor microenvironment is under severe chronic inflammatory stress, and inflammatory factors actively promote proliferation, invasion, angiogenesis, and immune suppression — greatly hindering effective treatment.

□ At the center of this inflammatory storm is HMGB1 (high mobility group box 1), a protein that is overexpressed in many cancers and drives tumor progression by activating inflammatory and immune-evasion pathways. Previous studies had confirmed that glycyrrhizin derivatives can inhibit HMGB1, but their anticancer potency remained modest. To overcome this limitation, the research team adopted a rational dual strategy: starting from 3-amino glycyrrhetinic acid (GN), they grafted anti-inflammatory cinnamic acid fragments onto one end of the molecule and progressively introduced benzyl esters, amino acids, and guanidyl groups onto the other end — synthesizing and screening forty candidate compounds.

□ The optimization paid off. A first-round hit, compound 22, showed the strongest activity against HCT116 colon cancer cells with an IC50 of 13.1 μmol·L⁻¹, but suffered from poor water solubility. After a second round of structural refinement, compounds 23 and 24 — featuring a water-soluble guanidyl group — emerged as lead molecules, with IC50 values of just 1.1 and 1.4 μmol·L⁻¹ against CT26 colon cancer cells, far outperforming both the parent compound glycyrrhizin and 5-FU, the first-line chemotherapy drug used as a positive control. At a concentration of only 3 μmol·L⁻¹, compound 23 nearly completely suppressed colony formation of CT26 cells.

□ Mechanistic studies revealed how the compound works: it arrests cancer cells at the G2/M phase of the cell cycle in a dose-dependent manner, disrupts mitochondrial membrane potential, triggers a burst of reactive oxygen species, and induces apoptosis — reducing key cell-cycle regulators including cyclin A2, cyclin B1, and CDK1. At the same time, compound 23 exhibits potent anti-inflammatory activity: it suppressed nitric oxide production with an IC50 of 1.1 μmol·L⁻¹ in CT26 cells, and Western blot analyses confirmed that it dose-dependently downregulates HMGB1, RAGE, TLR4, phospho-NF-κB, TNF-α, IL-6, IL-1, and COX-2, while blocking the downstream PI3K/AKT pathway.

□ Encouragingly, these effects translated in vivo. In a CT26 tumor-bearing mouse model, compound 23 reduced both tumor volume and tumor weight more effectively than 5-FU at equivalent doses, acting in a dose-dependent manner. Serum analysis confirmed the mechanism: treated mice showed markedly reduced levels of HMGB1, RAGE, TNF-α, and IL-6, indicating that the anticancer effect is at least partly achieved by taming inflammation within the tumor tissue. Acute toxicity testing established a favorable safety margin, with an approximate LD50 of 600 mg·kg⁻¹.

□ “Compound 23 not only strongly inhibits the proliferation of colon cancer cells, but also shows strong anti-inflammatory activity within the tumor microenvironment,” stated Professor Quanyi Zhao. “It therefore holds great potential as a candidate drug for anti-colorectal cancer therapy, and deserves further investigation as a foundation for future treatment development.”

□ This research was jointly conducted by the Institute of Medicinal Chemistry at the School of Pharmacy of Lanzhou University and the Medical Laboratory Center of Lanzhou University. Jianrong Liu and Jingke Zhang participated as co-first authors, and the findings were published in the *Chinese Journal of Natural Medicines* (2026, 24(9), 1129–1145; DOI: 10.1016/S1875-5364(26)61210-1), a peer-reviewed journal dedicated to natural products research published by the China Pharmaceutical University.

*Corresponding author: Prof. Quanyi Zhao (zhaoqy@lzu.edu.cn)*
*Paper: https://doi.org/10.1016/S1875-5364(26)61210-1*