Hexokinase 2 upregulation is associated with glycolytic reprogramming and neuroinflammation in hypoxic-ischemic brain damage: a therapeutic target for early intervention.
Overview
- Department of Radiology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Clinical Research and Translational Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Child Developmental Behavior, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Abstract
Background: Hypoxic-ischemic brain damage (HIBD) involves profound metabolic reprogramming, where aberrant glycolysis links to neuronal injury. This study aimed to identify and characterize glycolysis-related hub genes in HIBD.
Methods: Glycolysis-related differentially expressed genes (DEGs) were screened from the HIBD dataset GSE144456 by combining differential expression analysis, weighted gene co-expression network analysis (WGCNA), and a glycolysis gene set. Hub genes were further identified via enrichment and protein-protein interaction (PPI) network analyses and validated in an independent dataset (GSE23317) and our internal RNA-seq. The key hub gene was confirmed in a mouse HIBD model using RT-qPCR and Western blot. To perturb Hexokinase 2 (Hk2), 3-bromopyruvate (3-BrPA, 1 mg/
Results: Bioinformatics analysis identified Hk2 as a key hub gene that was consistently upregulated in HIBD. In vivo experiments demonstrated that both HK2 protein and mRNA levels were significantly elevated 24 hours after HIBD (P < 0.001). Double immunofluorescence staining further revealed that the upregulated HK2 was predominantly localized to Iba1+ microglia. Early administration of 3-BrPA reduced acute cerebral infarction volume (P < 0.001), improved neurological function scores (P < 0.001), and concurrently downregulated HK2 protein levels (P < 0.05). 3-BrPA treatment also significantly reduced lactate accumulation in the injured brain tissue (P < 0.001). It also suppressed the mRNA expression of pro-inflammatory cytokines (Tnf, Il1b, and Il6; all P < 0.001) and modulated the protein levels of inflammatory markers (iNOS, ARG1; P < 0.05 and P < 0.01, respectively). Moreover, this single early intervention significantly mitigated long-term brain tissue loss and improved motor coordination and exploratory behavior at 30 days post-injury (P < 0.05).
Conclusion: Hk2 is highlighted as a critical node associated with both glycolytic reprogramming and neuroinflammation in HIBD, with upregulation primarily in microglia. Early perturbation of glycolysis with 3-BrPA is associated with multifaceted benefits. Our findings link the Hk2-glycolysis axis to neuroinflammation, offering a rationale for exploring metabolic interventions in HIBD.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Data links
- ncbi.nlm.nih.gov/
geo — NCBI; found in the text, “Bioinformatics data sources and pretreatment”
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 8 authors, 5 keywords, 13 MeSH terms, 1 funder, 59 references.
Cite
This paper
Li, Y., Qin, C., Miao, C., Mu, R., Zhang, P., Zhang, B., Zhao, X., & Zhang, X. (2026). Hexokinase 2 upregulation is associated with glycolytic reprogramming and neuroinflammation in hypoxic-ischemic brain damage: a therapeutic target for early intervention. Frontiers in immunology, 17, 1837728. https://
BibTeX
@article{li2026hexokinas
author = {Li, Yue and Qin, Chi and Miao, Chenxu and Mu, Ronghao and Zhang, Penghua and Zhang, Bohao and Zhao, Xin and Zhang, Xiaoan},
title = {{Hexokinase 2 upregulation is associated with glycolytic reprogramming and neuroinflammation in hypoxic-ischemic brain damage: a therapeutic target for early intervention}},
journal = {Frontiers in immunology},
year = {2026},
month = jun,
volume = {17},
pages = {1837728},
publisher = {Frontiers Media SA},
issn = {1664-3224},
doi = {10.3389/
url = {https://
pmid = {42367795},
pmcid = {PMC13303037}
}
RIS
TY - JOUR
AU - Li, Yue
AU - Qin, Chi
AU - Miao, Chenxu
AU - Mu, Ronghao
AU - Zhang, Penghua
AU - Zhang, Bohao
AU - Zhao, Xin
AU - Zhang, Xiaoan
TI - Hexokinase 2 upregulation is associated with glycolytic reprogramming and neuroinflammation in hypoxic-ischemic brain damage: a therapeutic target for early intervention
T2 - Frontiers in immunology
J2 - Front Immunol
PY - 2026
DA - 2026/
VL - 17
SP - 1837728
SN - 1664-3224
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
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