Multi-Omics Integration in Stroke: Neuroinflammatory Endotypes, Immune Cell Crosstalk, and Precision Biomarker Discovery.

Stroke remains one of the leading causes of death and disability worldwide, yet its clinical management is constrained by substantial biological heterogeneity that single-biomarker and single-omics approaches fail to resolve. The integration of multiple molecular data layers, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and immunomics, offers a transformative framework for investigating the underlying neuroinflammatory mechanisms of different stroke subtypes and endotypes. In this review, we synthesize the current multi-omics evidence in stroke by examining how genetic variants propagate through regulatory and immune pathways and generate measurable molecular signatures and clinically relevant biomarkers. We investigate the roles of microglia, infiltrating monocyte-derived macrophages, astrocytes, neutrophils, T cells, and endothelial cells as interacting nodes in the neuroimmune network after stroke, and analyze how spatially resolved single-cell transcriptomics illuminate state-specific programs previously undetectable in bulk tissue analyses. We discuss how proteomics and metabolomics translate these cellular programs into actionable circulating biomarkers and examine emerging evidence on blood-brain barrier disruption and neurovascular unit remodeling as multi-omics-defined targets. We then explore AI and machine learning frameworks enabling the integration of heterogeneous, high-dimensional datasets for endotype classification, patient stratification, and therapeutic response prediction. Finally, we address translational barriers, including analytical standardization, multi-ancestry generalizability, and regulatory readiness, and propose a roadmap for precision stroke medicine based on systems immunology. The core conceptual point of this review is the shift from describing omics findings in stroke cases to redefining biologically meaningful neuroinflammatory endotypes and using multi-omics to enable precision cerebrovascular medicine.