Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop

  • Cell Death Differ. 2025 Feb 27. doi: 10.1038/s41418-025-01467-x.
Junjun Xiong  #  1 ,  Xuhui Ge  #  1  2  3 ,  Dishui Pan  #  1 ,  Yufeng Zhu  1 ,  Yitong Zhou  1 ,  Yu Gao  1 ,  Haofan Wang  1 ,  Xiaokun Wang  1 ,  Yao Gu  1 ,  Wu Ye  1 ,  Honglin Teng  4 ,  Xuhui Zhou  5  6  7 ,  Zheng Wang  8 ,  Wei Liu  9  10  11 ,  Weihua Cai  12
Affiliations
  • 1. Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2. Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
  • 3. Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China.
  • 4. Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5. Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China. [email protected].
  • 6. Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China. [email protected].
  • 7. Translational Research Centre of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Department of Orthopedics, Chinese PLA General Hospital, Beijing, China. [email protected].
  • 9. Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • 10. Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China. [email protected].
  • 11. Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China. [email protected].
  • 12. Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 40016338 DOI: 10.1038/s41418-025-01467-x
Abstract

Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA Sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal Ferroptosis in vitro and expanded infiltration of CD68+ macrophages/microglia, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, Deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of UCHL1 inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of UCHL1 and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.

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