Microvascular endothelial metabolic dysfunction drives cerebral edema through bioenergetic failure after ischemia-reperfusion.

Aim: Despite major advances in recanalization therapy, poor functional outcomes after ischemic stroke remain common. The central challenge is not only restoring blood flow but also overcoming the bioenergetic failure that can persist during reperfusion. This study aims to identify the missing link by defining how a metabolic-epigenetic cascade drives microvascular energetic collapse, thereby elucidating mechanisms underlying sustained cerebral edema and the no-reflow phenomenon following ischemia-reperfusion. Methods: We analyzed serum samples from patients with acute ischemic stroke to evaluate associations among lactate/pyruvate (L/P) ratios, functional outcomes, and cerebral edema. High-resolution magnetic resonance imaging (MRI) and FITC-dextran extravasation test in transient middle cerebral artery occlusion (tMCAO) model were used to determine whether glycolytic inhibition reduced edema. Single-cell RNA sequencing characterized endothelial cell subpopulations after stroke, and molecular experiments examined the effects of lactate accumulation on histone H3K18 lactylation (H3K18la) and downstream ATF4-DDIT4 signaling. Mitochondrial function, electron transport chain (ETC) activity, and necroptosis-related pathways were assessed in endothelial cells. Results: An elevated L/P ratio was strongly correlated with poor neurological outcomes and was closely linked to ischemia-reperfusion-induced cerebral edema. Reducing glycolytic flux and lactate production attenuated edema formation. Single-cell sequencing identified a post-stroke hyper-glycolytic endothelial subset characterized by mitochondrial dysfunction and necroptosis activation, with greater expansion in aged tMCAO mice. Lactate accumulation increased H3K18la in endothelial cells and activated the ATF4-DDIT4 pathway, which further impaired mitochondrial and ETC function. These changes established a self-amplifying pathological loop -glycolysis/H3K18la/ATF4-DDIT4 - that intensified bioenergetic failure while promoting RIPK3-dependent necroptosis and inflammation. Conclusions: Aberrant lactate metabolism not only serves as a prognostic biomarker but also provides a mechanistic link between metabolic insufficiency and epigenetic dysregulation through histone lactylation. Targeting the feedback loop involving H3K18la and ATF4-DDIT4 offers a promising therapeutic approach to limit cerebral edema and improve functional outcomes after ischemic stroke.