Abstract
BACKGROUND: Membrane lipids play a crucial role in brain function and cell signalling, and they serve as key biological substrates in inflammatory responses, thrombosis, and energy metabolism. Multiple clinical and molecular evidences suggest that membrane lipids are probably involved in the pathogenesis of ischemic stroke (IS). However, current knowledge about the membrane lipid landscape and its involvement in IS pathophysiology is limited. METHODS: We performed untargeted lipidomic analysis on erythrocyte membranes from 56 IS patients and 55 healthy controls. Integrated with gene expression and weighted gene co-expression network analysis, we identified dysregulated lipid signalling pathways and their contributions to IS pathophysiology. RESULTS: A total of 1392 erythrocyte membrane lipids were detected and quantified. Our results revealed significant impairment of membrane lipid homeostasis in IS patients, characterized by a marked reduction in glycerophospholipids (GPLs) and lysophospholipids (LPLs). Further analysis indicated that the impaired lipids were primarily concentrated in three disturbed signalling pathways, including the phospholipase A2-mediated GPL-LPL pathway, the phospholipase C-mediated inositol 1,4,5-trisphosphate/diglyceride pathway, and the sphingosine-1-phosphate (S1P)-S1P receptors pathway. Gene expression results indicated that these pathways were inhibited during the subacute phase of IS. Furthermore, these lipid signalling pathways form a highly interconnected network that collaboratively contributes to inflammation and thrombosis in IS, thereby influencing the progression and prognosis of the disease. CONCLUSION: Our findings reveal impaired erythrocyte membrane lipid homeostasis in IS, which implicates inflammatory processes and thrombosis in IS. This research offers new insights into the role of membrane lipids in IS pathogenesis, potentially informing future monitoring and therapeutic strategies.