YiQiFuMai ameliorates hypoperfusion-induced cerebral infarction by targeting the shear stress-PLBD1-glycolysis-angiogenesis axis

BACKGROUND: Hypoperfusion-induced cerebral infarction remains a significant therapeutic challenge due to limited treatment options. Yiqi Fumai (YQFM), a traditional Chinese medicine formula, has shown promise in treating cerebrovascular disorders, but its mechanisms in cerebral infarction remain unclear. PURPOSE: To investigate the therapeutic effects and underlying mechanisms of YQFM in hypoperfusion-induced cerebral infarction. STUDY DESIGN: This study combines machine learning analysis, animal experiments, and cellular mechanistic investigations. METHODS: Using an integrated approach combining machine learning analysis of clinical data, transcriptomics of rat brain tissue, computational fluid dynamics, microfluidics, in vivo experiments, and in vitro experiments, we investigated YQFM's effects on hypoperfusion-induced cerebral infarction. Cerebral blood flow, infarct volume, and neurological outcomes were assessed using multiple imaging modalities and behavioral tests. Single-cell transcriptomic analysis and transcriptomic analysis were performed to identify potential therapeutic targets. The mechanism was validated through in vitro experiments. RESULTS: , and enhanced neurological outcomes without toxicity. Mechanistically, we found that phospholipase B domain containing 1 (PLBD1) was downregulated after hypoperfusion-induced cerebral infarction and restored by YQFM treatment, in vitro experiments demonstrated that YQFM enhanced endothelial mechanotransduction in response to shear stress by upregulating PLBD1, leading to increased glycolysis and improved endothelial proliferation. We identified a potential "shear stress-PLBD1-glycolysis-angiogenesis" axis that mediates YQFM's therapeutic effects. This multidimensional approach not only advances the existing knowledge of endothelial function but also highlights PLBD1 as a promising therapeutic target for ischemic stroke. Furthermore, the integration of advanced methodologies, such as single-cell transcriptomics and computational fluid dynamics, provides a more comprehensive understanding of YQFM's therapeutic effects. CONCLUSION: YQFM treats hypoperfusion-induced cerebral infarction by modulating endothelial mechanotransduction and glycolysis to enhance collateral vessel formation and cerebral perfusion. This study provides mechanistic insights into YQFM's therapeutic action and highlights the potential of targeting the "shear stress-PLBD1-glycolysis-angiogenesis" axis for developing strategies to improve collateral circulation in hypoperfusion-induced cerebral infarction.