Insights into Metabolic-Inflammatory Dual-targeting Effects of Huangqi Guizhi Wuwu Decoction on Diabetic Hepatopathy via Regulation of the AMPK-FASN/PI3K-AKT Axis

Objective: Huangqi Guizhi Wuwu Decoction (HGWD), a Traditional Chinese Medicine prescription known for warming the meridians and promoting blood circulation, has shown therapeutic potential for diabetic hepatopathy (DH). However, the precise molecular mechanisms by which HGWD regulates hepatic lipid remodeling in DH remain unclear. This study aimed to investigate the therapeutic effects and underlying mechanisms of HGWD, with an emphasis on its dual modulation of lipid metabolism and inflammation. Methods and Results: DH mice were treated with low, medium, or high doses of HGWD for 8 weeks. Serum biochemical analyses and histopathological assessments confirmed the efficacy of HGWD, with the high-dose group demonstrating the most significant reductions in hyperglycemia, hepatic lipid accumulation, and liver injury. Lipidomics identified 118 dysregulated hepatic metabolites, predominantly fatty acyls associated with lipogenesis and pro-inflammatory eicosanoids. Network pharmacology and Western blot analyses revealed AMPK-FASN and PI3K-AKT as the core pathways targeted by HGWD. HGWD restored AMPK phosphorylation, suppressed FASN-mediated lipogenesis, and inhibited PI3K-AKT-driven inflammatory responses, thereby normalizing fatty acid synthesis, degradation, and arachidonic acid metabolism. It also reduced inflammatory markers and alleviated mitochondrial-ER lipid-signaling dysfunction. Molecular docking showed strong binding of key HGWD constituents, paeoniflorin and cinnamic acid, to proteins within the AMPK-FASN and PI3K-AKT pathways. Conclusions: Collectively, these findings demonstrate that HGWD exerts dual-pathway regulatory effects by reprogramming lipid metabolism via AMPK-FASN and attenuating inflammation through PI3K-AKT, providing a pharmacological basis for its use in DH and supporting the development of precision therapies for diabetic complications.