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

ABSTRACT 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.