Abstract
OBJECTIVE: This study aimed to elucidate the therapeutic mechanisms of the Shengdihuang-Huangqi (SDHHQ) herbal pair in type 2 diabetes mellitus (T2DM) by integrating network pharmacology, transcriptomics, and metabolomics, together with experimental validation, to identify key bioactive compounds and explore their potential targets. METHODS: Active components of SDHHQ were screened from multiple databases, potential targets were predicted through network pharmacology, and a compound-target network was constructed by cross-referencing with T2DM-related genes. KEGG and GO enrichment analyses were then performed to identify key signaling pathways. Transcriptomic profiling of liver tissues from T2DM rats was carried out using RNA sequencing, while serum analysis was conducted via metabolomics. Transcriptomic and metabolomic data were integrated to explore gene-metabolite associations and identify potential pathways of SDHHQ action. Experimental validation involved measurements of fasting blood glucose, serum lipid levels, histopathology, and hepatic gene expression in T2DM rats, as well as glucose uptake and glycogen synthesis assays in insulin-resistant HepG2 cells. RESULTS: Network pharmacology analysis identified six bioactive compounds-quercetin, kaempferol, formononetin, apigenin, catalpol, and acteoside-as potential major contributors to the therapeutic effects of SDHHQ against T2DM. In vivo experiments demonstrated that SDHHQ significantly ameliorated hyperglycemia, dyslipidemia, and tissue damage in T2DM rats. Multi-omics analysis and qPCR validation further indicated that SDHHQ ameliorates T2DM by modulating the insulin resistance, AMPK, and PPAR signaling pathways, thereby influencing hepatic glycogen synthesis and glucose uptake. CONCLUSIONS: In conclusion, SDHHQ ameliorates T2DM by modulating glucose metabolism through the INS/IRS2/AKT2 and FOXO1 pathways and lipid metabolism via the SREBP1c/FAS/ACC1 and PPARα/CD36 pathways, providing molecular evidence for its therapeutic potential.