Buwang Formula Regulates Microglial Metabolic Reprogramming and Modulates the mTOR/HIF-1α Pathway to Reduce Neuroinflammation in Diabetic Mice

Background: Microglial metabolic reprogramming drives neuroinflammation in Diabetes-associated cognitive dysfunction (DACD). This study aims to evaluate Buwang formula (BWF) effects on diabetic neuroinflammation and microglial metabolism. Methods: The chemical constituents present in BWF-containing cerebrospinal fluid (BWF-CCSF) were profiled by UHPLC-MS/MS, and putative targets were predicted via network pharmacology analysis. Diabetic db/db mice were treated with BWF, and behavioral, biochemical, and histopathological assessments were performed. The in vivo findings were further validated in BV2 cells exposed to high glucose (HG) and palmitic acid (PA). Cellular energy metabolism analysis was used to quantify dynamic changes in oxidative phosphorylation (OXPHOS) and glycolysis in BV2 cells, while flow cytometry and immunofluorescence were used to examine BV2 cell polarization. The expression levels of pathway-related proteins were examined by Western blot analysis. Results: A total of 15 chemical components were identified in BWF-CCSF. According to the network pharmacology prediction, the mTOR/HIF-1α pathway might participate in the effects exerted by BWF compounds that enter the brain. In diabetic mice, BWF notably suppressed the expression of pro-inflammatory factors and reduced the accumulation of pathological proteins within the hippocampal tissue, which improved learning and memory impairments, and these improvements were accompanied by suppressed activation of the mTOR/HIF-1α pathway and its downstream glycolysis. In BV2 cells exposed to HG and PA, BWF-CCSF treatment significantly increased OXPHOS and inhibited glycolysis, promoting a polarization toward M2 anti-inflammatory phenotype. Conclusions: BWF regulates microglial metabolic reprogramming and attenuates neuroinflammation, effects that are associated with modulation of the mTOR/HIF-1α pathway, and these findings suggest that BWF warrants further investigation as a potential therapeutic candidate for DACD.