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O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review)

  • Authors:
    • Zhenzhen Huang
    • Xin Liu
    • Ling Zhang
    • Yujie Lin
    • Xiangli Ma
    • Peiwu Li
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    Affiliations: Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 281
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    Published online on: August 4, 2025
       https://doi.org/10.3892/mmr.2025.13646
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Abstract

Sepsis is a life‑threatening condition triggered by dysregulated host immune responses, involving complex interactions among immune cell dysfunction, metabolic reprogramming and impaired autophagy. As a dynamic post‑translational modification of serine/threonine residues, the attachment of N‑acetylglucosamine (GlcNAc) via an oxygen linkage (O‑GlcNAcylation) serves as a central hub in the pathogenesis of sepsis by integrating immunometabolic adaptation and autophagy regulation. This modification, dynamically controlled by O‑GlcNAc transferase and O‑GlcNAcase, modulates immune cell activation, inflammatory signaling and pathogen clearance. In sepsis, aberrant O‑GlcNAcylation exacerbates organ damage by promoting pro‑inflammatory cytokine release and suppressing protective autophagy. Studies have highlighted its dual role: Enhancing O‑GlcNAcylation can bolster antiviral immunity, while targeted inhibition could mitigate bacteria‑induced hyperinflammation. Furthermore, O‑GlcNAcylation regulates the initiation, elongation and lysosomal fusion stages of autophagy by modifying key proteins, including beclin1, unc‑51‑like kinase 1 and synaptosome-associated protein 29, thereby influencing immune cell function. The present review also explores the mechanisms by which O‑GlcNAcylation modulates immune responses across diverse pathogens, namely bacteria, fungi, viruses and parasites, via signaling pathways such as NF‑κB and STAT, emphasizing the importance of site‑specific interventions and biomarker development. In conclusion, targeting O‑GlcNAcylation offers a potential novel direction for sepsis treatment. However, further exploration of its dynamic equilibrium in the precise regulation of the immune‑autophagy network is necessary.
View Figures

Figure 1

Pathophysiologic course of sepsis.
During the development of sepsis, the balance of the immune system
is disrupted. DAMP, damage-associated molecular pattern; NK,
natural killer; Treg, regulatory T.

Figure 2

Role of O-GlcNAcylation in the
initiation, nucleation, elongation and fusion stages of autophagy
and lysosomal activity. AMPK, AMP-activated protein kinase; ATG,
autophagy related; FIP200, FAK family kinase-interacting protein of
200 kDa; LC3, microtubule-associated protein 1A/1B-light chain 3;
O-GlcnAc, O-linked N-acetylglucosamine; O-GlcNAcylation, attachment
of GlcNAc via an oxygen linkage; OGA, O-GlcNAcase; OGT, O-GlcNAc
transferase; PI3K, phosphoinositide 3-kinase; PI3P,
phosphatidylinositol-3-phosphate; SNAP29, synaptosome-associated
protein 29; STX17, syntaxin 17; ULK1, unc-51 like autophagy
activating kinase 1; VAMP8, vesicle-associated membrane protein 8;
VSP, voltage-sensing phosphatase.

Figure 3

Role of O-GlcNAcylation in the immune
response to infection with different pathogens. BCR, B-cell
receptor; BLT1, LTB4 receptor 1; c-Rel, cellular-Rel; DFF45, DNA
fragmentation factor 45; EZH2, enhancer of zeste 2; fMLP,
N-formyl-methionyl-leucyl-phenylalanine; GM-CSF, granulocyte
macrophage-colony-stimulating factor; IAV, influenza A virus; IFN,
interferon; IFNG, IFN-g; iNOS, inducible nitric oxide synthase;
IRF, IFN regulatory factor 3; Lsp1, lymphocyte-specific protein 1;
LTB4, leukotriene B4; MAVS, mitochondrial antiviral signaling
protein; miR-15b, microRNA-15b; NFAT, nuclear factor of activated
T-cells; NK, natural killer; NKG2D, NK group 2D; O-GlcNAc, O-linked
N-acetylglucosamine; OGT, O-GlcNAc transferase; PI3K,
phosphoinositide 3-kinase; RIPK, receptor-interacting protein
kinase; RoRyt, retinoic acid receptor-related orphan receptor gt;
TET2, Tet methylcytosine dioxygenase 2; Th17, T helper 17.
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Copy and paste a formatted citation
Spandidos Publications style
Huang Z, Liu X, Zhang L, Lin Y, Ma X and Li P: O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review). Mol Med Rep 32: 281, 2025.
APA
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., & Li, P. (2025). O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review). Molecular Medicine Reports, 32, 281. https://doi.org/10.3892/mmr.2025.13646
MLA
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., Li, P."O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review)". Molecular Medicine Reports 32.4 (2025): 281.
Chicago
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., Li, P."O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review)". Molecular Medicine Reports 32, no. 4 (2025): 281. https://doi.org/10.3892/mmr.2025.13646
Copy and paste a formatted citation
x
Spandidos Publications style
Huang Z, Liu X, Zhang L, Lin Y, Ma X and Li P: O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review). Mol Med Rep 32: 281, 2025.
APA
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., & Li, P. (2025). O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review). Molecular Medicine Reports, 32, 281. https://doi.org/10.3892/mmr.2025.13646
MLA
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., Li, P."O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review)". Molecular Medicine Reports 32.4 (2025): 281.
Chicago
Huang, Z., Liu, X., Zhang, L., Lin, Y., Ma, X., Li, P."O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review)". Molecular Medicine Reports 32, no. 4 (2025): 281. https://doi.org/10.3892/mmr.2025.13646
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