ABSTRACT NUMBER: ESOC2026A1794 INTEGRATED MULTI-OMICS FACTOR ANALYSIS IDENTIFIES EARLY MOLECULAR SIGNATURES OF BRAIN INJURY IN ISCHEMIC STROKE

Abstract Background and aims Acute ischemic brain injury could be reflected in systemic molecular dynamics that may support patient monitoring and stratification. We leveraged serial multi-omics in acute stroke to identify circulating molecular signatures capturing key mechanisms of brain injury, such as reperfusion injury, oxidative stress, and inflammation. Methods We performed mass spectrometry-based plasma proteomics and metabolomics in 502 patients with acute ischemic stroke from the Precision Medicine in Stroke (PROMISE) study. Samples were collected upon admission (day 1) and the following morning (day 2). We used Multi-Omics Factor Analysis (MOFA), an unsupervised integrative method that uncovers latent factors across multiple omics layers, to identify molecular factors associated with NIHSS scores, final infarct volume, and 90-day mRS. Results At both day 1 and 2, MOFA revealed factors that significantly correlated with NIHSS, final infarct volume, and 90-day functional outcome with stronger associations for day 2. These factors were characterized by proteins involved in complement activation (C9), acute-phase response (CRP, SAA1), neutrophil activation (S100A9) and endothelial injury (VWF), together with inflammation-related choline-containing lipids such as linoleoylcholine. Enrichment analysis of these top molecular drivers identifed neutrophil-mediated immune responses, complement and coagulation cascades, and lipid metabolism as key biological pathways. Individual top-ranked proteins and metabolites driving the injury-associated factor correlated with NIHSS scores and infarct volume and independently predicted 90-day mRS scores. Conclusions Omics integration by MOFA uncovers latent molecular signatures linked to brain injury in acute ischemic stroke, providing mechanistic insight with the potential to ultimately supporting patient stratification, brain injury monitoring and targeted therapeutic intervention. Conflict of interest Wei Cao: nothing to disclose Figure 1 - belongs to Methods Figure 2 - belongs to Results