Astrocytic Ketogenesis Protects Central Nervous System Injury via CPT1A Stabilization and Epigenetic Regulation

Following central nervous system (CNS) injury, reactive astrocytes proliferate and encapsulate the lesion to facilitate repair. However, the specific metabolic characteristics remain unknown. Here, through integrated single‐cell and spatial transcriptomics, we uncovered a subset of astrocytes that undergo enhanced lipid and ketone metabolic reprogramming following spinal cord injury (SCI). The ketone body β‐hydroxybutyrate (β‐OHB) inhibited autophagic degradation of carnitine‐palmitoyltransferase‐1A (CPT1A) via P300‐mediated lysine β‐hydroxybutyrylation (Kbhb). Astrocyte‐specific deletion of Cpt1a led to impaired wound healing, reduced axonal sparing and worsened locomotor recovery after SCI, effects rescued by exogenous β‐OHB. Mechanistically, ketogenesis promotes wound repair and lipid metabolic reprogramming, forming a positive feedback loop via H3K9bhb‐dependent epigenetic remodeling in astrocytes after SCI. Furthermore, ketogenic diet (KD) promoted tissue repair across multiple CNS injury models. Clinically, elevated β‐OHB levels were associated with better tissue preservation and functional recovery in SCI patients. Collectively, our findings underscore the critical role of astrocytic lipid metabolic and epigenetic reprogramming after CNS injury and identify KD as a promising therapeutic strategy.