Integrated metabolomics and computational analysis suggest that a Sanghuangporus vaninii-based formulation alleviates T2DM in mice and modulates hepatic morphine-3-glucuronide axis.

This study aimed to investigate the therapeutic material basis and mechanisms of a Sanghuangporus vaninii-based functional food formulation (FSV) in type 2 diabetes mellitus (T2DM) using an integrated approach combining chemical profiling, metabolomics, and computational biology. Chemical profiling of FSV was performed using UPLC-QTOF/MS, followed by network pharmacology to identify core bioactive constituents. The therapeutic effects of FSV were evaluated in a T2DM mouse model (n = 10 per group, 4-week intervention, with metformin as a positive control) by assessing hyperglycemia, dyslipidemia, and hepatic steatosis. Hepatic metabolomics was conducted to explore metabolic changes, and molecular docking was employed to investigate potential interactions between key metabolites and diabetes-related targets. UPLC-QTOF/MS analysis identified 766 compounds, with 22 core flavonoids (e.g., apigenin, tangeritin) selected via network pharmacology. In T2DM mice, FSV intervention significantly ameliorated hyperglycemia, dyslipidemia, and hepatic steatosis. Liver metabolomics revealed targeted modulation of the glucagon signaling pathway, marked by reduced levels of β-D-fructose 6-phosphate and oxaloacetate. Notably, endogenous morphine-3-glucuronide (M3G) was identified as a notable hepatic metabolite. Molecular docking suggested that M3G may potentially interact with PIK3CA/EGFR based on computational prediction, while FSV was associated with reduced hepatic M3G levels in T2DM mice. However, these in silico findings require experimental validation. These findings suggest that FSV not only delivers bioactive flavonoids but also modulates specific endogenous metabolites such as M3G, offering new chemical and metabolic insights into functional food-based diabetes therapy.