Jiedu Tongluo Tiaogan Formula Modulates Glycolipid Metabolism in Type 2 Diabetes via Pyroptosis: Network Pharmacology and In Vivo Analysis

Type 2 diabetes mellitus (T2DM) is characterized by pancreatic β-cell dysfunction and insulin resistance, with pyroptosis emerging as a key contributor to β-cell loss. Jiedu Tongluo Tiaogan Formula (JTTF), a traditional Chinese medicine (TCM), has shown clinical efficacy in T2DM management, but its mechanism linking pyroptosis remains unexplored. This study integrates UPLC-MS/MS, network pharmacology, and in vivo experiments to elucidate JTTF's anti-diabetic mechanisms. UPLC-MS/MS identified 441 compounds in JTTF, predominantly alkaloids, flavonoids, phenols, and terpenoids. Network pharmacology revealed JTTF's multi-target effects on T2DM-associated pyroptosis, particularly via the NLRP3/Caspase-1/GSDMD pathway. In diabetic mice, JTTF dose-dependently reduced fasting blood glucose, insulin resistance, and dyslipidemia, while restoring pancreatic β-cell morphology. Mechanistically, JTTF suppressed NLRP3 inflammasome activation, downregulated Caspase-1 and GSDMD expression, and attenuated IL-1β/IL-18 release. Notably, this study provides the first evidence of JTTF's anti-pyroptotic effects in T2DM, highlighting its unique ability to modulate glycolipid metabolism and inflammatory cell death concurrently. These findings underscore JTTF's translational promise for preserving β-cell function and suggest future exploration of non-classical pyroptosis pathways. Our work bridges traditional medicine and molecular pharmacology, paving the way for clinical trials and integrative T2DM therapies.