Single-cell and single-nucleus transcriptomics in ischemic stroke: cellular mechanisms and therapeutic implications

Abstract

Ischemic stroke remains a major cause of death and long-term disability and is defined by complex, dynamic pathophysiological processes involving diverse cell types and interconnected molecular networks. In recent years, single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) have provided unmatched resolution for dissecting these processes. A growing body of studies has applied these approaches to ischemic stroke, generating extensive insight into cellular heterogeneity, molecular regulation, and disease-associated cell states. This review systematically integrates current evidence from sc/snRNA-seq studies, with a primary focus on brain-intrinsic mechanisms after ischemic stroke. Existing findings are organized across major pathophysiological domains, including immune and inflammatory responses, blood-brain barrier (BBB) disruption and angiogenesis, regulated cell death, metabolic dysregulation, aging and cellular senescence, and neuroregeneration and remyelination. Beyond these canonical mechanisms, we summarize emerging applications of sc/snRNA-seq in extra-CNS systems, distinct biological contexts, and stroke-related complications. We also highlight how sc/snRNA-seq has been used to investigate therapeutic mechanisms, including physical and neuromodulatory interventions, pharmacological agents, cell-based therapies, and bioengineered delivery systems. Together, this review provides a structured synthesis of how sc/snRNA-seq has advanced the understanding of ischemic stroke biology by identifying disease-relevant cell states, refining mechanistic targets, and informing future translational development.