Inflammation-centered neurovascular-immune-metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation.

Ischemic stroke evolves beyond arterial occlusion through an inflammation-centered network linking neurovascular dysfunction, immune remodeling, metabolic reprogramming, and regulated cell death. These interactions are organized across the hyperacute, acute, subacute, and chronic phases. Hyperacute energy failure, excitotoxicity, thromboinflammation, pericyte contraction, and capillary stalling can sustain microcirculatory no-reflow despite recanalization. Acute injury is characterized by blood-brain barrier disruption, innate immune amplification, mitochondrial stress, as well as ferroptotic, necroptotic, pyroptotic, and proposed cuproptotic pathways. Subacute recovery involves debris clearance, immune resolution, angiogenesis, metabolic adaptation, and oligodendrocyte-lineage repair, whereas chronic outcomes reflect persistent inflammation, white-matter remodeling, and neural plasticity. Cell-specific metabolism and brain-border and systemic immune-metabolic communication further shape injury and recovery. Experimental evidence is distinguished from findings in human blood, thrombectomy-derived samples, imaging, and brain tissue. Therapeutic translation requires stage-matched interventions compatible with reperfusion and rehabilitation, clinically realistic post-onset dosing, mechanistic biomarkers, and appropriate safety evaluation. This framework links early microvascular rescue with immune resolution, metabolic recovery, and network repair.