Metabolic reprogramming orchestrates microglial fate in cerebral ischemia-reperfusion injury: a spatiotemporal...

Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological cascade that paradoxically exacerbates neurological damage following revascularization therapy for acute ischemic stroke (AIS). The pathogenesis of CIRI is intricately linked to dysregulated neuroinflammation, with microglia-the resident innate immune cells of the central nervous system-serving as central orchestrators of this response. Emerging evidence indicates that microglia undergo profound metabolic reprogramming encompassing glucose metabolism, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, and NAD⁺ homeostasis, which fundamentally dictates their functional polarization and consequent neuroinflammatory outcomes. Rather than existing as discrete pro-inflammatory versus reparative phenotypes (classically referred to as M1/M2), microglia exhibit a continuum of activation states with distinct metabolic signatures that evolve dynamically across spatiotemporal dimensions following CIRI. Here, we systematically synthesize current knowledge on the core molecular mechanisms underlying microglial metabolic reprogramming, including the ACOD1/itaconate pathway, the glycolysis-OxPhos balance, and NAMPT-mediated NAD⁺ homeostasis. We critically examine the intricate crosstalk between these metabolic pathways and neuroinflammatory signaling cascades, revealing how metabolic checkpoints serve as integrative nodes that decode microenvironmental cues into functional outputs. Building on this mechanistic foundation, we evaluate emerging intervention strategies targeting metabolic reprogramming, stratified by intervention modality and translational readiness, with emphasis on agents in active clinical development. Finally, we identify prevailing challenges-including spatiotemporal heterogeneity, cell-specific targeting requirements, and clinical translation barriers-and outline future directions integrating single-cell omics, systems biology approaches, and advanced delivery systems. This comprehensive analysis aims to provide a refined conceptual framework and highlight promising therapeutic avenues for mitigating CIRI through strategic modulation of microglial immunometabolism.