Background: Previous studies have shown Radix Hedysari (RH)’s gastroprotective potential, but its active components and mechanisms remain uncharacterized. This study aimed to identify RH’s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified eight flavonoids via HPLC. Network pharmacology screened targets/pathways using TCMSP, GeneCards databases. In vivo validation employed cisplatin–induced injury models in Wistar rats (n = 10/group). Assessments included: behavioral monitoring; organ indices; ELISA (MTL, VIP, IFN–γ, IgG, IL–6, TNF–α etc.); H&E; and Western blot:(SCF, c–Kit, p65). Dose–effect correlations were analyzed by PLS–DA. Results: Content determination indicated that Calycosin–7–glucoside and Ononin were notably enriched on both the n–BuOH part and the EtOAc part. Network pharmacology identified 5 core flavonoids and 8 targets enriched in IL–17/TNF signaling pathways. n–BuOH treatment minimized weight loss vs. MCG, increased spleen/thymus indices. n–BuOH and HPS normalized gastrointestinal, immune, inflammatory biomarkers (p < 0.01 vs. MCG). Histopathology confirmed superior mucosal protection in n–BuOH group vs. MCG. Western blot revealed n–BuOH significantly downregulated SCF, c–kit, and p65 expressions in both gastric and intestinal tissues (p < 0.001 vs. MCG). PLS–DA demonstrated Calycosin–7–glucoside had the strongest dose–effect correlation (VIP > 1) with protective outcomes. Conclusions: The n–BuOH fraction of RH is the primary bioactive component against chemotherapy–induced gastrointestinal injury, with Calycosin–7–glucoside as its key effector. Protection is mediated through SCF/c–Kit/NF–κB pathway inhibition, demonstrating significant dose–dependent efficacy. These findings support RH’s potential as a complementary therapy during chemotherapy.

Backbround: “Fructus Arctii–licorice” herb pair is used in several formulas for oral-mucosa diseases, but the mechanism of action has not been studied. In this work, we investigated the mechanism of action of “Fructus Arctii–licorice” herb pair on the treatment of oral-mucosa diseases at the molecular level based on bioinformatics, network pharmacology, and molecular-docking techniques. Methods: The active ingredients of “Fructus Arctii–licorice” herb pair were screened and downloaded from the TCMSP database, and their target information was obtained. The gene chips of oral-mucosa diseases patients were obtained from the GEO database, and the differential genes were analyzed by GEO2R. The targets of oral-mucosa diseases were obtained by applying GeneCards, OMIM, and DrugBank databases, and the key targets of the “Fructus Arctii–licorice” herb pair to treat oral-mucosa diseases were obtained by taking the intersection of the three. The STRING platform was used for protein–protein interaction (PPI) network analysis to screen the core targets, the DAVID database was used for GO and KEGG pathway-enrichment analysis, and the molecular-docking technique was used to analyze the binding between the active ingredients of “Fructus Arctii–licorice” herb pair and the core targets. Results:“Fructus Arctii–licorice” herb pair for the treatment of oral-mucosa diseases involved 61 key targets, 251 gene functional information, and 78 signaling pathways. The core targets were MMP9, TNF, IL6, PTGS2, and STAT3, which functioned primarily through the AGE-RAGE, TNF, IL-17, PI3K-Akt, NF-κB, JAK-STAT, and other signaling pathways. Molecular-docking results showed that the top 10 active ingredients in the "drug-component-target-disease-pathway" network diagram had good binding ability to the core targets, among which MMP9-naringenin, IL6-glyasperin B, TNF-arctigenin, PTGS2-glabridin, and STAT3-liquiritigenin had the optimum docking effect. Conclusions:The results of this study provided a comprehensive explanation of the active ingredients, targets, and mechanisms of action of “Fructus Arctii–licorice” herb pair in treating oral-mucosa diseases. This pair primarily acted by modulating inflammatory, tumor, immune, and metabolic pathways and may provide directions for subsequent studies.