Ethnopharmacological relevance: Xiehuang San (XHS) is a classical Chinese herbal formula with analgesic, anti-inflammatory, gastrointestinal-regulating and hypoglycemic effects, but its specific regulatory mechanisms remain incompletely understood.
Aim of the study: To evaluate the effects of XHS on T2DM, with a particular focus on its metabolic and molecular mechanisms.
Materials and methods: C57BL/6J mice were induced with T2DM using a high-fat diet combined with streptozotocin. T2DM mice were treated with XHS for 4 weeks to assess blood glucose control and metabolism. Serum metabolomics were analyzed by UPLC-Q-TOF/MS. Network pharmacology integrated drug-metabolite-disease associations. Molecular docking and dynamics simulations assessed the binding of active compounds to targets. RT-qPCR and Western blot were used to determine gene and protein expression levels. An in vitro model was established to validate the effects of XHS on T2DM.
Results: XHS significantly improved T2DM pathology. Compared to the diabetic Mod group, XHS reduced fasting blood glucose levels, enhances glucose tolerance and improves insulin resistance and sensitivity. 24 dysregulated metabolites were corrected after treatment. Network pharmacology predicted that the key target of XHS in T2DM treatment is the CLCF1-STAT3 pathway. Licochalcone B, Wogonin and Apigenin are predicted to exhibit strong binding affinity for this pathway. Both in vitro and in vivo models, XHS effectively inhibits the activation of the CLCF1-STAT3 signalling pathway and protects insulin signalling.
Conclusion: This study combines metabolomics and network pharmacology to reveal that XHS exerts anti-diabetic effects by remodeling glycerophospholipid metabolism and inhibiting CLCF1-STAT3 signaling. These findings support the application of XHS in the treatment of T2DM.
Keywords: CLCF1; Lipid metabolism; Metabolomics; STAT3; Type 2 diabetes mellitus; Xiehuang San.
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