Jiangtang Tiaozhi Formula Relieves HFD ‐Induced Obesity Related Type 2 Diabetes by Inhibiting the cGAS ‐ STING Pathway

ABSTRACT Jiangtang Tiaozhi Formula (JTTZF), a traditional Chinese medicine (TCM) prescription, has been widely used clinically for obesity‐related type 2 diabetes (T2D) for many years that can clear heat, release turbidity, open up stagnation and unblock meridians. Several previous clinical studies have demonstrated its effectiveness in decreasing glucose and lipid metabolism disorders, weight loss, and improving chronic inflammation and insulin resistance (IR); however, the exact pathways through which it influences obesity‐related T2D require further investigation. This study aims to establish a systematic approach to the pharmacological basis of JTTZF and assess the therapeutic efficacy and its potential mechanisms of JTTZF in ameliorating obesity‐related T2D induced by high‐fat diet (HFD). Using ultra‐high‐performance liquid chromatography‐mass spectrometry (UHPLC–MS), we identified JTTZF metabolites. Obesity‐related diabetic models were established in both mice and zebrafish. The treatment effects were evaluated through haematoxylin and eosin (H&E) and oil Red O (ORO) staining, transmission electron microscopy and assessment of glucose/lipid metabolism indicators. Finally, the specific molecular mechanism underlying JTTZF's efficacy against this condition was comprehensively analysed via in vivo experimental verification. UHPLC–MS/MS identified 371 compounds in JTTZF, with 14 prototype constituents (e.g., demethyleneberberine, epiberberine) absorbed in the liver, linked to anti‐diabetic activity. In HFD‐induced zebrafish and C57BL/6 mice models, JTTZF significantly ameliorated glucose and lipid metabolic disorders. Histopathological and ultrastructural analyses revealed attenuated hepatic steatosis, reduced lipid droplets and restored mitochondrial integrity. JTTZF also suppressed hepatic inflammation by down‐regulating proinflammatory cytokines. Mechanistically, JTTZF inhibited the cyclic GMP–AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway, decreasing phosphorylation of cyclic GMP–AMP synthase–stimulator of type I interferon genes (TBK1) and nuclear factor‐κB (NF‐κB), while STING inhibitor C‐176 and Metformin also displayed similar effects. These findings suggest that JTTZF is a therapeutic agent in inhibiting STING‐restored metabolic homeostasis for the management of obesity‐related T2D via the cGAS‐STING/TBK1/NF‐κB pathway.