Anti-colorectal cancer actions of Glycyrrhiza uralensis Fisch. and its underlying mechanism via HPLC integration and network pharmacological approaches.

Background: The therapeutic and prognostic outcomes for colorectal cancer (CRC) remain unsatisfactory. Among multiple reported bioactive functionalities of Glycyrrhiza uralensis Fisch. one vital recently reported activity is its therapeutic role against numerous cancers but limited information is available related to its underlying key mechanisms and therapeutically active ingredients, especially against CRC treatment.

Objective: The aim of current study aims is to reconnoiter G. uralensis pharmacological basis and primary molecular mode of action in treating CRC.

Methods: For examining the G. uralensis active ingredients and underlying mechanism investigation against CRC including, potential anti-CRC phytochemicals, targets, and related signaling pathways, HPLC and Network-pharmacology analysis techniques was employed, respectively. Whereas, for binding capabilities of active components to their targets, molecular-docking, molecular dynamic simulation technique employed and cell proliferation assays screened the best anti-CRC components, followed by biological function experiments on SW480 cells for verification. Finally, the SW480-xenograft model and subsequent related experiments further confirmed the effect of Liquiritin on CRC.

Results: Seven compounds were identified from G. uralensis through HPLC. Network pharmacology and molecular docking results indicated that G. uralensis components exhibited significant anti-cancer effects. These effects were mediated through cancer and MAPK-related signaling pathways, targeting TP53, SRC, STAT3, and PIK3CA proteins. In-vitro experiments showed that liquiritin had better anti-CRC effects compared to other components as it significantly repressed the SW480 propagation, development of colony, relocation, and invasion. Additionally, liquiritin has been shown to significantly reduce tumor size in tumor-bearing mice by targeting p53 and inhibiting the p38 MAPK pathway.

Conclusion: In G. uralensis, main API is liquiritin that target CRC tumorigeneses via inhibition of p53 and p38 MAPK, thus can be used for CRC therapy. The findings provide a solid pharmacological basis and potential therapeutic targets for G. uralensis in the treatment of CRC.