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

Cell Death & Differentiation volume 32, pages 1214–1230 (2025)Cite this article

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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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Fig. 1: Astrocytic glycolysis was upregulated after SCI.
Fig. 2: UCHL1 interacted with PFKFB3.
Fig. 3: UCHL1 deubiquitinated and stabilized PFKFB3.
Fig. 4: Conditional deletion of Uchl1 in astrocytes inhibited astrocytic glycolysis and aggravated neuronal ferroptosis.
Fig. 5: Conditional deletion of Uchl1 in astrocytes hindered functional recovery after SCI.
Fig. 6: UCHL1 promoted neuronal survival and functional recovery by increasing expression of PFKFB3 after SCI.
Fig. 7: A glycolysis/H4K8la/UCHL1 positive feedback loop in astrocytes after SCI.
Fig. 8: Overexpression of UCHL1 improved functional recovery in vivo after SCI.

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Data availability

CUT&Tag data have been deposited at GEO: GSE266984. Most datasets supporting the conclusions of this study are included within this article and the additional files. Any additional information required to reanalyzed the data reported in this work is available upon reasonable request. More detailed materials are in the supplementary file.

Change history

  • 01 May 2025

    In this article the supplementary fig 6 has been updated.

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Acknowledgements

We would like to thank the Core Facility of the First Affiliated Hospital of Nanjing Medical University for its help in the experiment.

Funding

This work was sponsored by the National Natural Science Foundation of China (Grant Nos. 82172426, 82372394 and 82302677), Shanghai Sailing Program (23YF1458000), Shanghai Chenguang Program (22CGA43), Natural Science Foundation of Jiangsu Province (BK20241986) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX23_1949).

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Author notes

  1. These authors contributed equally: Junjun Xiong, Xuhui Ge, Dishui Pan.

Authors and Affiliations

  1. Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Junjun Xiong, Xuhui Ge, Dishui Pan, Yufeng Zhu, Yitong Zhou, Yu Gao, Haofan Wang, Xiaokun Wang, Yao Gu, Wu Ye, Wei Liu & Weihua Cai

  2. Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China

    Xuhui Ge, Xuhui Zhou & Wei Liu

  3. Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai, China

    Xuhui Ge, Xuhui Zhou & Wei Liu

  4. Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Honglin Teng

  5. Translational Research Centre of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xuhui Zhou

  6. Department of Orthopedics, Chinese PLA General Hospital, Beijing, China

    Zheng Wang

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Contributions

Conceptualization, WC, WL, ZW and XZ; methodology, JX, XG, and DP.; investigation, JX, XG, WC, WL, and ZW; visualization, XG, DP, Yufeng Zhu, Yitong Zhou, and Yu Gao; funding acquisition, WC and WL; project administration, WC, WL and XZ; writing-original draft, JX, HW, XW, Yao Gu and WY; writing-review & editing, JX, HT, ZW, and XZ; supervision, WC and WL. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Xuhui Zhou, Zheng Wang, Wei Liu or Weihua Cai.

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The study was approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Nanjing Medical University and conducted in accordance with the Guide for the Care and Use of Laboratory Animals.

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Xiong, J., Ge, X., Pan, D. et al. Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop. Cell Death Differ 32, 1214–1230 (2025). https://doi.org/10.1038/s41418-025-01467-x

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