2. Academic Validation
  3. Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop

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

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. zhouxuhui@smmu.edu.cn.
  • 6 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China. zhouxuhui@smmu.edu.cn.
  • 7 Translational Research Centre of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhouxuhui@smmu.edu.cn.
  • 8 Department of Orthopedics, Chinese PLA General Hospital, Beijing, China. wangzheng301@163.com.
  • 9 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. liuweiorth@njmu.edu.cn.
  • 10 Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China. liuweiorth@njmu.edu.cn.
  • 11 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China. liuweiorth@njmu.edu.cn.
  • 12 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. caiwhspine@njmu.edu.cn.
  • # 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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