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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

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

  • Dishui Pan1
  • Haoming Shu2
  • Rui Gao3
  • Yilong Ren2
  • Wu Ye1
  • Xuhui Ge1,3,4
  • Yao Gu1
  • Yufeng Zhu1
  • Xiaokun Wang1
  • Honglin Teng5
  • Xuhui Zhou3,4
  • Wei Liu1,3,4,5
3 more authors
  • Yang Gao6
  • Jianquan Zhao3
  • Weihua Cai1
6 affiliations
  1. 1Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  2. 2Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  3. 3Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
  4. 4Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China.
  5. 5Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  6. 6Department of Orthopedics, Fourth Medical Centre of Chinese PLA General Hospital, Beijing, China.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{pan2026astrocytic,
  title = {{Astrocytic Ketogenesis Protects Central Nervous System Injury via CPT1A Stabilization and Epigenetic Regulation.}},
  author = {Dishui Pan and Haoming Shu and Rui Gao and Yilong Ren and Wu Ye and Xuhui Ge and Yao Gu and Yufeng Zhu and Xiaokun Wang and Honglin Teng and Xuhui Zhou and Wei Liu and Yang Gao and Jianquan Zhao and Weihua Cai},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78393},
  url = {https://europepmc.org/article/MED/42902976},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Astrocytic Ketogenesis Protects Central Nervous System Injury via CPT1A Stabilization and Epigenetic Regulation.
AU  - Dishui Pan
AU  - Haoming Shu
AU  - Rui Gao
AU  - Yilong Ren
AU  - Wu Ye
AU  - Xuhui Ge
AU  - Yao Gu
AU  - Yufeng Zhu
AU  - Xiaokun Wang
AU  - Honglin Teng
AU  - Xuhui Zhou
AU  - Wei Liu
AU  - Yang Gao
AU  - Jianquan Zhao
AU  - Weihua Cai
PY  - 2026
DA  - 2026/10/20
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78393
UR  - https://europepmc.org/article/MED/42902976
AB  - 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.
SN  - 2198-3844
ER  -