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

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.