Xuanfei Baidu Decoction and Its Active Component Glycyrrhizic Acid Ameliorate Insulin Resistance in Type 2 Diabetes via JNK/JAK/STAT Axis Inhibition

Background: Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and chronic inflammation, yet current single-target therapies inadequately address these interconnected pathologies. Xuanfei Baidu decoction (XFBD), originally developed for COVID-19, is known to inhibit JNK and JAK/STAT pathways and may offer a multi-target strategy. Methods: A high sugar diet (HSD) induced Drosophila T2DM model was treated with XFBD or its active component glycyrrhizic acid (GA). Phenotypic assays, metabolomics, 16S rRNA sequencing, qPCR, transgenic reporter flies, network pharmacology, and computational docking/dynamics simulations were performed. Results: XFBD dose-dependently alleviated HSD-induced developmental delay, hyperglycemia, insulin resistance (restored dilp2/3/5, InR, 4EBP expression and AKT phosphorylation), glycolipid disorders, and oxidative stress. Metabolomics identified 79 reversed metabolites enriched in T2DM-relevant pathways (D-amino acid, BCAA, TCA cycle). XFBD suppressed aberrant JNK and JAK/STAT activation, independent of gut microbiota modulation. GA recapitulated these effects in vivo. Conclusions: XFBD and GA ameliorate insulin resistance and metabolic dysregulation via JNK/JAK-STAT axis inhibition, providing a preclinical rationale for their therapeutic application in T2DM and related metabolic syndrome outcomes.