Uncovering the key role of energy metabolism and establishing metabolite-based prognostic biomarkers in ischemic stroke patients undergoing intravenous thrombolysis therapy

Abstract: OBJECTIVE: This study aimed to investigate the metabolic changes related to intravenous thrombolysis (IVT) in ischemic stroke (IS) patients, to explore the potential mechanisms involved in recombinant tissue plasminogen activator therapy, and to identify metabolite-based prognostic biomarkers. SUBJECTS AND METHODS: This study initiated a Mendelian randomization (MR) analysis with IS as the exposure and 871 metabolites as the outcomes. Subsequently, we recruited 46 IS patients undergoing IVT and 22 healthy controls (HCs). The 90-day functional outcomes of patients were assessed according to the modified Rankin Scale scores. Plasma samples from patients before (pregroup) and after (postgroup) IVT and HC group were analyzed for liquid chromatography-tandem mass spectrometry. RESULTS: The MR results showed causal relationships between IS and 46 metabolites. In the comparisons conducted between the pre- and HC groups, the post- and pregroups, and the unfavorable outcome and favorable outcome groups, 120, 57, and 10 different metabolites were screened, respectively. KEGG pathway analysis showed the most significant pathway alterations occurred in amino acid metabolism and carbohydrate metabolism. The combination of 3,5-dihydroxybenzoic acid, lauroylcarnitine, 5β-androstan-3-one-17β-carboxylic acid methyl ester; and 3-methyl-2-oxovaleric acid had an excellent ability to predict the prognosis of patients with IVT (AUC = 0.850). CONCLUSIONS: Our study confirmed the existence of metabolic disturbances following IS using genetics and metabolomics. Energy metabolism dysregulation participated in IS pathophysiology and IVT process, significantly influencing clinical outcomes. This metabolite-based predictive model needs large-scale validation to improve its generalizability.