O-GlcNAcylation and phosphorylation are two key protein PTMs that regulate a variety of physiological and pathological processes through dynamic competition or synergy. O-GlcNAcylation involves the addition of a single GlcNAc group to Ser or Thr residues, whereas phosphorylation involves the addition of phosphate groups, often at the same or adjacent sites, resulting in a competitive or cooperative regulatory relationship between the two mechanisms (19). For example, in metabolic regulation, O-GlcNAcylation inhibits the Ser9 phosphorylation of glycogen synthase kinase-3β, thereby reducing the hyperphosphorylation of Tau protein, which may protect against neurodegenerative diseases such as Alzheimer's disease (20,21). Similarly, the Ser40 phosphorylation of tyrosine hydroxylase (TH) promotes dopamine synthesis, whereas O-GlcNAcylation reduces TH activity by inhibiting phosphorylation at this site, thereby affecting L-DOPA levels (22). In addition, O-GlcNAcylation can increase the activity of glycogen phosphorylase, suggesting that synergistic effects may exist between these two PTMs in certain contexts (23).

In the pathological process of sepsis, the balance between O-GlcNAcylation and phosphorylation markedly influences the regulation of inflammatory responses and cell death. Recent studies have shown that O-GlcNAcylation can inhibit phosphorylation-driven pro-inflammatory signaling by targeting key inflammation-related proteins. For example, the O-GlcNAcylation of gasdermin D (GSDMD) inhibits its phosphorylation-dependent activation, thereby attenuating lipopolysaccharide (LPS)-induced pyroptosis, a mechanism that may protect against vascular endothelial injury in sepsis (24). Similarly, homeodomain-interacting protein kinase 2 (HIPK2) inhibits hyperinflammation by promoting the acetylation of NF-κB via the phosphorylation of histone deacetylase 3 (HDAC3), while O-GlcNAcylation may affect this pathway indirectly by regulating the activity or stability of HIPK2 (25). The NF-κB acetylation promoted by the HIPK2-mediated phosphorylation of HDAC3 has been shown to ameliorate colitis-associated colorectal cancer and sepsis in mice. In another study, Toll-like receptor 4 (TLR4) was shown to activate ERK1/2 phosphorylation, leading to the downregulation of Kruppel-like factor 4, thereby exacerbating the inflammatory response in sepsis (26).

In sepsis, phosphorylation is often associated with the amplification of pro-inflammatory and cell death signals. For example, peptidylprolyl cis/trans isomerase, NIMA-interacting 1 exacerbates the inflammatory response in septic shock by promoting the phosphorylation of p38 MAPK, which increases the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. O-GlcNAcylation can counteract this effect by competitively modifying the same or adjacent sites of p38 MAPK, thereby preventing its phosphorylation and blocking downstream inflammatory signaling (27,28). Notably, O-GlcNAcylation and phosphorylation may act synergistically in certain contexts. For example, O-GlcNAc modification has been shown to increase glycogenolysis by promoting the phosphorylation of glycogen phosphorylase L during energy stress (23). In summary, the dynamic interplay between O-GlcNAcylation and phosphorylation in sepsis reflects a precisely regulated balance that controls inflammatory intensity, cell death patterns and metabolic adaptation. Targeting this interaction may offer novel strategies for the treatment of sepsis.

There is a complex, cross-regulatory relationship between O-GlcNAcylation and ubiquitination, both of which are involved in cellular stress responses, metabolic regulation and disease progression. O-GlcNAc modification affects the stability, activity and interactions of proteins by the dynamic addition or removal of GlcNAc groups, thereby influencing the ubiquitination process (29). For example, O-GlcNAcylation can increase the stability of key proteins by inhibiting their ubiquitination; the O-GlcNAcylation of the circadian regulators brain and muscle ARNT-like 1 and circadian locomotor output cycles kaput prevents their ubiquitin-mediated degradation, thereby maintaining the normal functioning of the biological clock (30). In addition, the synergistic or antagonistic effects of O-GlcNAcylation and ubiquitination play critical roles in processes such as DNA damage repair and cancer metabolism (31,32). The activity of certain E3 ubiquitin ligases, such as members of the cullin-RING ligase (CRL) family, can be regulated by O-GlcNAc modifications, thereby affecting the ubiquitination levels of their substrate proteins (33). The ubiquitin-proteosome system itself is highly complex, with various ubiquitin chain types, including lysine (Lys)48- and Lys63-linked chains, and dynamic modification patterns. These features form a multi-level interaction network with O-GlcNAcylation to coordinate cellular responses to stresses such as oxidative stress and nutrient deprivation (29,34).

The cross-regulation between O-GlcNAcylation and ubiquitination plays a key role in modulating the intensity of the inflammatory response and maintaining cellular homeostasis. Studies have shown that O-GlcNAc modification can dynamically modulate pro-inflammatory signaling pathways by targeting key components of the ubiquitination system. For example, in macrophages, O-GlcNAc-modified NOD-like receptor X1 (NLRX1) downregulates IL-1β expression by interacting with inhibitor of κB kinase α (IKK-α) and inhibiting its ubiquitination-dependent activation, thereby potentially limiting tissue damage due to excessive inflammatory responses in sepsis (35). In addition, the E3 ubiquitin ligase tripartite motif containing 27 (TRIM27) exacerbates sepsis-related oxidative stress and endothelial dysfunction by promoting the ubiquitin-mediated degradation of peroxisome proliferator-activated receptor γ (PPARγ), and O-GlcNAc modification may counteract the pro-inflammatory effects of TRIM27 by stabilizing PPARγ protein levels (30,36). Notably, the diversity of ubiquitination systems, including different chain linkages such as Lys48- and Lys63-linked chain types, contributes to the dual regulatory features observed in sepsis: Lys48-linked ubiquitination typically targets proteins for proteosomal degradation, helping to clear damaged proteins, whereas Lys63-linked ubiquitination amplifies inflammation by activating pathways such as the NF-κB pathway (29,37). O-GlcNAc modification may balance the inflammatory phenotype of macrophages by selectively regulating the activity of specific E3 ligases, such as E3 ubiquitin-protein ligase COP1, and affecting the ubiquitination status of transcription factors such as CCAAT/enhancer binding protein β (38).

Ubiquitination often serves as a central node for pro-inflammatory and cell death signaling in sepsis, while O-GlcNAc modification may exert a protective effect through multi-level regulatory mechanisms. For example, microbial infection-induced endothelial cell dysfunction is associated with the aberrant ubiquitination of a variety of proteins, such as NADPH oxidase 4 (NOX4), whose stability is regulated by ubiquitination, and its overexpression exacerbates oxidative stress (36,37). O-GlcNAc modification may reduce the production of reactive oxygen species (ROS) by directly modifying NOX4 or regulating the activity of its E3 ligases, such as TRIM27, analogous to its modulatory role in the CRL family ubiquitin ligases involved in DNA damage repair (33). Small-molecule drugs targeting the ubiquitination system, such as deubiquitinase inhibitors, have been shown to modulate the inflammatory cascade in sepsis (39). Similarly, the development of OGT inhibitors or activators may provide new therapeutic strategies by modulating the O-GlcNAc-ubiquitination axis. Notably, there may be synergistic effects between these pathways: For example, O-GlcNAcylation may enhance the stability of NLRX1, promoting its binding to IKK-α and thereby indirectly inhibiting the ubiquitin-dependent activation of the IKK complex; this regulatory homeostasis may exhibit distinct regulatory characteristics at different stages of sepsis (35). In conclusion, the interplay between O-GlcNAcylation and ubiquitination constitutes a complex regulatory network in sepsis. Further elucidation of the underlying mechanism may lay a foundation for the development of targeted interventions to prevent inflammatory imbalance and organ injury.

There is extensive cross-regulation between O-GlcNAc modification and both DNA and histone methylation, which together contribute to the maintenance of epigenetic homeostasis and the regulation of gene expression. Studies have shown that OGT directly modifies DNA methyltransferase 1 through glucose-dependent O-GlcNAcylation, thereby inhibiting its activity, reducing the overall level of genomic methylation and affecting transposon silencing (40,41). At the histone level, OGT is recruited to specific chromatin regions by disruptor of telomeric silencing 1-like, a histone methyltransferase, where it catalyzes the O-GlcNAcylation of histone H2B, which works synergistically with histone H3 Lys79 (H3K79) methylation to regulate gene transcriptional activation (31). In addition, metabolic signals, such as glucose availability, are integrated into the epigenetic regulatory network via O-GlcNAc modification. For example, the c-Myc oncoprotein modulates mitochondrial metabolism and O-GlcNAc cycling, influencing the activity and subcellular localization of DNA and RNA demethylases, thereby linking cellular metabolic state to epigenetic reprogramming (42).

The crosstalk between O-GlcNAcylation and methylation regulates epigenetic reprogramming and metabolic adaptation, which affects the inflammatory response and organ injury. Dysregulation of this epigenetic modification is particularly prominent in monocytes from patients with sepsis and is strongly associated with the aberrant expression of pro-inflammatory cytokines such as TNF-α and IL-6, as well as organ dysfunction (43). In addition, the synergistic interaction of histone methylation with O-GlcNAcylation has a dual role in sepsis: During the endotoxin tolerance stage, G9a-mediated H3K9 methylation and DNA methylation contribute to silencing of the TNF-α gene (44), while O-GlcNAc modification dynamically regulates the expression of pro- and anti-inflammatory genes by regulating DOT1-like histone Lys methyltransferase-dependent H3K79 methylation (31). This multilevel epigenetic-metabolic-ubiquitination regulatory network provides a new paradigm for targeting immunometabolic imbalances in sepsis.

In conclusion, O-GlcNAcylation forms a multi-dimensional regulatory network with other PTMs, including phosphorylation, ubiquitination and methylation, that supports a shift in sepsis treatment from a single anti-inflammatory mode to a systematic regulation based on the dynamic integration of the PTM network. This integrated perspective could provide enable the reversal of immunometabolic imbalances in sepsis.

Neutrophils are key cells of the innate immune system that rapidly migrate to sites of bacterial infection and remove pathogens via phagocytosis, the release of ROS and necrosis. Neutrophils are the initial responders to injury and infection, and the prognosis of sepsis is poor when neutrophil migration is impaired (74). In both animal models and patients with advanced sepsis, neutrophil function is notably compromised, as evidenced by diminished bacterial clearance, reduced reactivity, decreased ROS production and a significant reduction in neutrophil numbers within infected tissues (75).

O-GlcNAcylation has been found to significantly influence neutrophil chemotaxis and cell migration. For example, treatment with the chemoattractant N-formylmethionyl-leucyl-phenylalanine significantly elevates O-GlcNAcylation levels, thereby promoting neutrophil chemotaxis and migration (76). In addition, glucosamine (GlcN) promotes O-GlcNAcylation by increasing the availability of UDP-GlcNAc, which is the donor substrate for OGT; GlcN enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting enzyme glutamine-fructose-6-phosphate transaminase 1, effectively bypassing it and boosting UDP-GlcNAc production (77). Mechanistically, enhanced O-GlcNAcylation promotes Rac- and phosphoinositide 3-kinase-dependent chemotaxis. Rac is an key small GTPase that regulates neutrophil mobilization by activating downstream MAPK signaling and promoting the phosphorylation of lymphocyte specific protein 1 at Ser243 (78–80). These signaling pathways are critical for neutrophil migration and effector functions. O-GlcNAcylation is inducible in neutrophils and modulates their dynamic responses, potentially providing a novel therapeutic target for the treatment of sepsis.

Macrophages play a key role in resistance to bacterial infections by eliminating pathogens through various mechanisms, including the activation of inducible nitric oxide synthase (iNOS) to produce nitric oxide (NO). NO is a gaseous signaling molecule with antibacterial properties, capable of inhibiting bacterial metabolic enzymes, thereby impairing bacterial viability. In response to bacterial infection or inflammatory stimuli, macrophages increase iNOS expression, thereby increasing NO production (81). NF-κB is a key regulator of the inflammatory response in macrophages and can be modified via O-GlcNAcylation. In RAW264.7 macrophage-like cells, the interaction of OGT with murine Sin3A disrupts NF-κB activation and downregulates iNOS gene expression upon LPS stimulation (82). In microglia, O-GlcNAcylation of the NF-κB subunit cellular-Rel (c-Rel) promotes the formation of the c-Rel-p50 heterodimer and increases iNOS production (83). Notably, the response of the NF-κB subunit p65 to O-GlcNAcylation differs markedly from that of c-Rel. Thiamet-G, a potent and selective inhibitor of OGA, exerts anti-inflammatory effects by promoting the O-GlcNAcylation of p65 in microglia, which subsequently modulates its nuclear localization and reduces the expression of inflammatory genes (84).

Inflammatory diseases such as sepsis are characterized by elevated glucose metabolism in immune cells. Despite macrophages exhibiting increased glycolytic activity and pentose phosphate pathway activation during inflammation, endotoxin exposure inhibits HBP activity, resulting in decreased protein O-GlcNAcylation. Loss of OGT promotes the innate immune response and exacerbates inflammation in sepsis. Specifically, OGT-mediated O-GlcNAcylation of receptor-interacting protein kinase (RIPK)3 at Thr467 disrupts its interaction with RIPK1 and RIPK3 proteins, thereby inhibiting downstream innate immune responses, necroptosis and antibacterial activity (85).

CD8⁺ T cells are essential for cell-mediated immunity. Upon acute infection, naive CD8⁺ T cells differentiate into effector cells following antigen stimulation. These effector cells eliminate bacteria by releasing granules containing perforins and granzymes, and secreting cytokines such as interferon (IFN)-γ and TNF-α (86,87). This immune response involves the phosphorylation of various intracellular signaling proteins. Protein O-GlcNAcylation often acts synergistically with phosphorylation (16). Lopez Aguilar et al (88) demonstrated that O-GlcNAcylation was dynamically elevated in murine CD8⁺ T cells during Listeria infection and in vitro differentiation, with activated effector cells exhibiting increased global levels in vivo, and memory-like cells exhibiting even higher levels (including distinct high-molecular weight modifications) in vitro. Proteomics revealed that O-GlcNAc in effector-like cells primarily targets transcription/translation machinery (such as ribosomal proteins) to enable rapid proliferation, while in memory-like cells it modifies transcriptional regulators, mRNA processing factors and tRNA synthetases, suggesting roles in establishing a poised state. Notably, O-GlcNAc contributes to the ‘histone code’ in both subsets, implicating it in epigenetic regulation of T cell function.

O-GlcNAcylation plays a key regulatory role in the immune response triggered by bacterial infection by dynamically modifying inflammation-related proteins. Pathogen-associated molecular patterns, such as bacterial LPS, can increase O-GlcNAcylation levels in endothelial cells, thereby exacerbating inflammation via the activation of inflammatory signaling pathways (89). At the molecular level, the OGT-mediated glycosylation of NLRX1 facilitates its interaction with IKK-α and promotes the expression of IL-1β in M1 macrophages (35). In parallel, O-GlcNAcylation of the NLRP3 inflammasome not only directly regulates pyroptosis but also promotes the release of inflammatory cytokines by enhancing the activity of the NIMA related kinase 7/NLRP3 axis (90,91). Furthermore, this PTM can create a positive feedback loop, whereby the O-GlcNAcylation of STAT3 further amplifies pro-inflammatory signaling by enhancing JAK2/STAT3 pathway signaling activity (92,93). As an upstream regulator, the phase separation process of TNF receptor-associated factor 6 may also contribute to this regulatory network. Notably, inhibition of O-GlcNAcylation has been shown to effectively block STAT3- and forkhead box protein O1-mediated oxidative stress-induced apoptosis (93–95), suggesting that targeting this modification may be a promising strategy for the alleviation of hyperinflammation during bacterial infections.

These findings suggest that targeting O-GlcNAc modifications may represent a novel therapeutic strategy for the treatment of sepsis by optimizing immune cell function and reducing the tissue damage caused by excessive inflammation.

O-GlcNAcylation has been implicated in the differentiation of T helper (Th)17 cells during fungal infections. Naive CD4⁺ T cells can differentiate into Th1, Th2, Th17 and Treg cells (96). The downregulation of OGT through microRNA-15b has been shown to inhibit Th17 cell differentiation, thereby contributing to the pathogenesis of multiple sclerosis (97). In addition, elevated O-GlcNAc levels have been shown to promote the secretion of IL-17A by Th17 cells and upregulate the production of lipid ligands for the transcription factor RAR-related orphan receptor γt in diet-induced obese mice (98). Furthermore, in Treg cells, O-GlcNAc-mediated post-translational modifications of the T-cell receptor (TCR) have been demonstrated to increase the stability of forkhead box P3 and activate STAT5, effects that act synergistically to control Treg cell homeostasis and function (96).

Notably, fungal O-GlcNAc metabolism itself directly affects pathogenicity. As a key signaling molecule, GlcNAc regulates morphological transitions, the expression of virulence factors and environmental adaptation in a variety of fungi such as Fusarium. For example, deletion of the OGT homologous gene FpOGT in Fusarium proliferatum inhibits the expression of glucose metabolism-related genes, such as glucokinase, resulting in restricted fungal growth, a downregulated stress response and markedly reduced virulence (99). In addition, GlcNAc has been demonstrated to be a key metabolic target for fungal pathogenesis since it regulates cell wall synthesis, biofilm formation and host tissue invasion pathways (100,101). From a therapeutic perspective, interventions targeting GlcNAc sensing and metabolism, such as GlcNAc analogs or metabolic engineering, have been shown to effectively reduce the virulence of pathogenic fungi (102).

Therefore, in sepsis complicated by fungal infection, the combined modulation of host O-GlcNAc levels to enhance Th17-mediated antifungal immunity while inhibiting fungal GlcNAc-dependent virulence pathways may offer a synergistic therapeutic strategy. Future studies are necessary to further elucidate the molecular mechanisms of the host-fungus O-GlcNAc interaction network and to develop dual regulatory strategies to optimize immunometabolic balance.

Macrophages play a crucial role in the innate immune system, particularly for the early detection of and response to viral infections. Research indicates that O-GlcNAcylation in macrophages is essential for the recognition of RNA viruses. These viruses are detected by cytosolic retinoic acid-inducible gene I-like receptors (RLRs), particularly retinoic acid-inducible gene I and melanoma differentiation-associated gene 5. Upon viral recognition, these receptors engage mitochondrial antiviral signaling protein (MAVS), which activates IFN regulatory factor (IRF)3 and promotes the production of type I IFN (103). In mouse bone marrow-derived macrophages, the absence of OGT disrupts MAVS-dependent RLR signaling and reduces inflammatory cytokine expression (104). Research has further shown that O-GlcNAcylation is crucial for modulating immune responses and increasing infection resistance in macrophages. During influenza A virus infection, O-GlcNAcylation regulates the inflammatory response by modulating the activity of specific transcription factors.

Specifically, O-GlcNAcylation at the Ser430 residue of IRF5 is necessary for its Lys63-linked ubiquitination, which promotes IRF5 activation by facilitating nuclear translocation and interaction with the E3 ubiquitin ligase TRAF6. This modification drives downstream proinflammatory cytokine production during influenza infection (105). Thus, both IRF3 and IRF5 undergo O-GlcNAcylation and ubiquitination, which are crucial for the regulation of macrophage-mediated inflammatory responses following influenza infection. Balancing these modifications is essential to ensure the appropriate intensity of the immune response while preventing excessive inflammation.

Natural killer (NK) cells are crucial components of the innate immune system, responsible for targeting and eliminating virus-infected cells. O-GlcNAcylation has been shown to modulate the function of NK cells as a PTM; specifically, the elevated O-GlcNAcylation of NK cells attenuates their cytotoxicity. Notably, certain molecules, such as the glutathione S-transferase-soluble HLA-G1α chain fusion protein, inhibit O-GlcNAcylation in NK cells, thereby enhancing their cytotoxic function (106).

NK group 2D (NKG2D) is an activating receptor on NK cells that facilitates the recognition and elimination of virus-infected cells presenting stress-induced ligands associated with major histocompatibility complex class I molecules (107). The cytotoxic function of NKG2D-expressing NK cells is regulated by the transcription factor enhancer of zeste 2 (EZH2), a core subunit of polycomb repressive complex 2. Inhibition of EZH2 has been shown to accelerate the maturation of NK cells and improve their killing ability. Notably, EZH2 contains five O-GlcNAcylation sites, which are pivotal for its stabilization and function (108–110).

Another transcription factor that induces cytotoxicity by regulating the O-GlcNAcylation of NK cells is c-Myc. It upregulates the expression of granzyme B, thereby increasing the cytotoxic activity of NK cells against virus-infected cells. O-GlcNAcylation helps to maintain the stability and function of c-Myc. The substrate for this modification, UDP-GlcNAc, is generated through glycolysis and the glutamine metabolic pathway. Glutamine depletion reduces UDP-GlcNAc levels in NK cells, subsequently impacting c-Myc function and diminishing cytotoxic activity (111). Thus, O-GlcNAc modification potentially boosts NK cell immune responses, aiding in the elimination of infected cells and protecting against the progression of sepsis.

B cells are activated via the B-cell receptor (BCR) on their surface, a process that is regulated by O-GlcNAcylation. This PTM affects the YN proto-oncogene, an Src family tyrosine kinase, and its interaction with spleen tyrosine kinase to initiate BCR signaling (112). In addition, the O-GlcNAcylation of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and NF-κB further amplifies B cell activation (113). Following BCR crosslinking, the interaction between O-GlcNAc-modified lymphocyte-specific protein 1 (Lsp1) and protein kinase C-β1 is crucial for the regulation of apoptosis in activated B cells. The O-GlcNAcylation of Lsp1 at Ser209 facilitates its phosphorylation at Ser243, thereby modulating Lsp1 function (114). Also, the dysregulation of EZH2 activity or aberrant O-GlcNAcylation may impair antibody production in B cells, indicating the importance of O-GlcNAcylation in the modulation of B cell function and antibody responses (115).

CD8⁺ cytotoxic T cells identify and destroy infected cells during viral infections. NF-κB and c-Myc are essential transcription factors in the activation of CD8⁺ T cells, and TCR-mediated stimulation induces their O-GlcNAcylation. The O-GlcNAcylation of c-Rel enhances its binding to the CD28 response element, resulting in the production of proinflammatory cytokines, including IL-2, IFN-γ and granulocyte macrophage-colony-stimulating factor. In addition, site-specific O-GlcNAcylation stabilizes c-Myc, while the inhibition of OGT decreases c-Myc levels (116,117). Furthermore, NFATc1 is mainly O-GlcNAcylated in the cytosol, and translocates to the nucleus after TCR activation. The O-GlcNAc modification of NFAT has been demonstrated to be crucial for its nuclear translocation and function, as the inhibition of OGT decreases TCR-induced IL-2 production and CD69 expression (113). These findings highlight the importance of O-GlcNAcylation in T cells. The inhibition of OGT has also been shown to affect the transcriptional activity of NF-κB in T cells, with the p65 subunit of NF-κB undergoing O-GlcNAcylation (113,118). In addition, the O-GlcNAcylation of DNA fragmentation factor 45 shields proteins from caspase-mediated cleavage during DNA damage-induced T-cell apoptosis, indicating its protective role against apoptotic cell death in T cells (119).

Modulating O-GlcNAc glycosylation levels or its downstream signaling pathways may help to address immune imbalances in patients with sepsis, suppress excessive inflammation, prevent organ dysfunction and ultimately improve clinical outcomes.

The dual role of O-GlcNAcylation in host anti-parasitic immunity and parasite self-regulation has become increasingly evident. This involves an interaction between the regulation of host immune cell function and the metabolic dependence of the parasite on O-GlcNAc pathways. In the anti-parasitic immunity of the host, O-GlcNAc contributes to key pathways that regulate type 2 immune responses. For example, the O-GlcNAcylation of STAT6 in intestinal epithelial cells forms the first line of defense against helminth infection by driving tuft cell proliferation and the release of gasdermin C-dependent alarmins (120). Restoration of STAT6 activation partially rescues the impaired immune responses to helminth infection in OGT-deficient mice, which exhibit defective STAT6 signaling and intestinal villus dysplasia (121). In addition, mast cell function is closely associated with O-GlcNAc modification: In Trichomonas vaginalis infection, leukotriene B4 (LTB4) secreted by the parasite binds to LTB4 receptor 1 on mast cells, elevates O-GlcNAc levels and promotes NADPH oxidase-dependent migration, degranulation and IL-8 secretion (122). However, Tet methylcytosine dioxygenase 2 (TET2)-mediated O-GlcNAcylation affects mast cell differentiation and cytokine production by regulating chromatin accessibility (123). These findings suggest that O-GlcNAc contributes to the anti-parasitic response through the multifaceted regulation of host immune cell functions, including Th2 polarization, epithelial barrier defense and mast cell effector functions.

At the biological level, glycosylation modifications, including O-GlcNAc-related pathways, are essential for the survival, development and pathogenicity of parasites. For example, Plasmodium falciparum relies on the HBP to produce glycosylphosphatidylinositol-anchored proteins, which are critical for the invasion of red blood cells and immune evasion. Therefore, blocking this pathway can lead to the growth arrest of Plasmodium at the schizont stage (124). Although Cryptosporidium lacks certain glycosylases, it compensates by hijacking host glycosylation resources to perform its protein modifications (125). In addition, glycosylation in various parasites, such as Plasmodium and Toxoplasma gondii, affects host immune recognition by altering the function of surface proteins (126,127). Notably, there is an interaction between host and parasite O-GlcNAc metabolism: Parasites may disrupt the glycosylation homeostasis of host immune cells by secreting metabolites such as GlcNAc, while host-targeted drugs against key enzymes involved in parasite glycosylation, such as glutamine:fructose-6-phosphate transaminase (GFAT) in the HBP, can simultaneously inhibit parasite growth and enhance immune clearance (124,127).

In summary, O-GlcNAcylation affects infection outcomes through host-parasite bidirectional regulation: It regulates host type 2 immune responses and effector cell functions through targets such as STAT6 and TET2, while parasites rely on glycosylation pathways to complete their developmental cycles and evade host immunity. Future studies should aim to further elucidate the parasite-specific O-GlcNAc modification network and explore dual intervention strategies, such as the development of GFAT inhibitors combined with immunomodulators, to synergistically enhance anti-parasitic immunity and block pathogen metabolism-dependent virulence mechanisms.