Abstract
Ischemic stroke, a leading cause of global disability and mortality, remains inadequately treated beyond reperfusion, with persistent translational failures in neuroprotection. We posit metabolic reprogramming in ischemic stroke (MRIS) as the unifying pathophysiological driver, where acute compensatory glycolysis collides with enzymatic lipid peroxidation to ignite neuroinflammation and early deficits. This metabolic crisis transcends neuron-centric models, integrating single-cell heterogeneity with bidirectional brain-peripheral crosstalk: hepatic ketogenesis releases neuroprotective β-hydroxybutyrate; adipose lipolysis fuels inflammatory storms; and gut dysbiosis disrupts barrier integrity, amplifying neuroinflammation. MRIS progresses through temporally stratified phases. An acute glycolytic-excitotoxic crisis and nicotinamide adenine dinucleotide (NAD(+)) depletion trigger neuroimmune dysfunction. Subacute lipid peroxidation cascades trigger ferroptosis and microglial polarization, whereas chronic-phase recovery of executive networks is scaffolded by sirtuin-mediated mitochondrial biogenesis and the interplay between adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR). Spatial metabolomics and single-cell omics decode cell-type-specific vulnerabilities, revealing astrocytic lipid droplets, microglial succinate accumulation, and neuron-glia lactate shuttles as targetable nodes. Chronobiology further dictates therapeutic windows: lactate dehydrogenase A (LDHA) inhibition mitigates hyperacute acidosis, while NAD(+) salvage pathways optimize chronic mitochondrial plasticity. We propose that metabolic reprogramming is a central amplifier of both ischemic injury and recovery, linking cerebral vascular occlusion to systemic organ dysfunction. By reframing stroke within a vascular-metabolic continuum, MRIS shifts the paradigm from a neuron-centric view to one of systemic bioenergetic failure, accounting for past translational gaps and opening pathways for precision therapies, from pentose phosphate pathway modulation to nanoparticle-based metabolite delivery and microbiome interventions. In this framework, metabolic plasticity becomes not just a consequence but a therapeutic target, transforming stroke from an untreatable vascular event to a modifiable metabolic disorder.