Astrocytic Sirt2-Mediated Delactylation Limits Blood-Spinal Cord Barrier Reconstruction after Spinal Cord Injury

Restoration of the blood-spinal cord barrier (BSCB) is required for substantial neurological improvement after spinal cord injury (SCI). Astrocytes are integral to this barrier and, after injury, undergo glycolytic adaptation accompanied by lactate accumulation. Whether a lactate-linked modification program in astrocytes participates in BSCB repair has remained unresolved. Here, we identify astrocytic delactylation as a brake on BSCB repair. Sirtuin2 (Sirt2), a delactylase, was strongly induced in astrocytes at the lesion border, and its expression paralleled the pathological expansion of microvessels. Selective deletion of Sirt2 in astrocytes increased lactylation, produced a lactate-rich metabolic state, attenuated inflammatory astrocyte programs, enhanced repair-associated features, and reinforced BSCB repair. These changes further reduced inflammatory infiltration and promoted neuronal retention, increased 5-hydroxytryptamine-positive fiber density, and improved locomotor recovery. Pharmacological Sirt2 inhibition produced similar vascular and locomotor benefits. Mechanistically, Sirt2 loss elevated H4K8la occupancy at the hepatocyte growth factor (Hgf) locus and promoted Hgf transcription, thereby facilitating BSCB repair. Astrocyte-specific Sirt2 ablation also weakened CD8⁺ T-cell-related inflammatory activity after SCI. Collectively, our findings position astrocytic Sirt2-dependent delactylation as a negative epigenetic-metabolic regulator of BSCB reconstruction and support astrocytic delactylation as a therapeutic target for SCI.