Network pharmacology and untargeted metabolomics reveal the mechanisms of Bushen Kaixuan Tongluo formula in diabetic kidney disease

Bushen Kaixuan Tongluo Formula (BKT), a clinically validated Traditional Chinese Medicine, has shown promising renoprotective effects in diabetic kidney disease (DKD) patients. This study investigated the therapeutic mechanisms of BKT in DKD using an integrated approach combining network pharmacology and untargeted metabolomics in db/db mice. Network pharmacology identified 338 bioactive components in BKT targeting 389 DKD-related genes, with key pathways including AGE-RAGE, HIF-1, MAPK, and PI3K-Akt signaling, as well as autophagy. BKT treatment significantly improved renal function (reduced ACR), ameliorated glucose/lipid metabolism (lowered GSP, INS, HOMA-IR, TC, FFA), and attenuated renal pathology (reduced glomerulosclerosis, tubular injury, and fibrosis). Untargeted metabolomics revealed 26 renal and 28 urinary differential metabolites (VIP > 1.0, P < 0.05), with enrichment in autophagy, PPAR signaling, linoleic acid metabolism (kidney), and TCA cycle/thiamine metabolism (urine). Key metabolites such as α-dimorphecolic acid (renal), thiamine pyrophosphate (urinary), and LysoPC (18:4) were implicated in BKT's renoprotective effects. These findings demonstrate that BKT alleviates DKD through multi-target modulation of metabolic, inflammatory, and stress-response pathways, with synergistic actions predicted by network pharmacology and validated by metabolomics. This study provides a scientific foundation for clinical application of BKT in DKD treatment.