Upregulation of glycolysis-associated GLUT and enzyme expression drives the proliferation and activation of T cells and the secretion of cytokines such as IL-2. GLUT and HK2 are vital enzymes in the glycolytic process (33). Glycolytic reprogramming involves increased expression of glucose transporter proteins, particularly GLUT1, which increases glucose uptake and allows immune cells to compete for glucose in a nutrient-restricted environment, and increased glucose uptake usually promotes viral replication (34, 35). The CD4⁺ T cells infected with human immunodeficiency virus type 1 (HIV-1) show increased glucose and glutamine metabolism due to the high-level GLUT1, which enhances HIV-1 infection (36, 37). Importantly, blockade of GLUT1 signaling or siRNA-mediated GLUT1 downregulation significantly impairs the HIV-1 infection in human T cells (38). Dengue virus (DENV) also induces the expression of GLUT1 and HK2 to promote glucose uptake and the downstream glycolytic processes to favor viral replication (39). In the rhinovirus (RV)-infected cells, viral replication is dependent on the availability of glucose and glutamine, which is affected by increasing glycogenolysis and upregulating GLUT1 expression (17). The envelope protein of white spot syndrome virus (WSSV) hijacks GLUT1 to promote viral infection (40). Furthermore, the Epstein-Barr virus (EBV) LMP1 protein can enhance transcription of GLUT1, which promotes aerobic glycolysis and the tumorigenic growth of NPC cells through the mTORC1/NF-κB signaling (41). The elucidation of interplay between GLUT1 and viruses will provide a direction for the development of effective antiviral strategies.

HK2 is an important enzyme in the glycolytic pathway and a kinase that modifies the phosphorylation of proteins to regulate immune signaling pathways. HK2 can activate the NF-κB signaling pathway by phosphorylating and degrading IκB. It has been demonstrated that aberrantly activated aerobic glycolysis in tumor cells promotes the segregation and binding of HK2 from mitochondria to cytoplasmic IκB, where HK2 acts as a protein kinase to phosphorylate IκB, leading to IκB degradation and NF-κB activation-dependent PD-L1 expression to escape tumor immunity (42) ( Figure 1 ). Notably, the NF-κB p65 plays a key role in the HBx-induced spontaneous hepatocellular carcinoma. The hepatitis B virus (HBV) x protein can activate the NF-κB signaling via the p65 phosphorylation by HK2 to promote immunoevasion of the virus and enhance glycolysis, further activating PI3K/Akt signaling to increase hepatocyte proliferation (43). HK2 and lactate can suppress the activation of the retinoic acid-inducible gene I (RIG-I)-mitochondrial antiviral signaling protein (MAVS) pathway by inhibiting MAVS. HK2 and glycolysis-derived lactate also play important roles in the immunoevasion of HBV and the regulation of energy metabolism in innate immunity during HBV infection. A previous study showed that HBV isolates MAVS from RIG-I by forming a ternary complex including hexokinase (HK), which inhibits the RLR signaling pathway through LDHA-dependent lactate production (44). Influenza A virus (H1N1) utilizes HK2 and the pyruvate kinase M2 (PKM2) to enhance glycolysis and further promote viral replication (45). These studies highlight the importance of the HK enzyme in regulating viral infection through the regulation of innate immune signals, revealing the possibility of a potential antiviral target.

Lactate dehydrogenase (LDH) is a crucial enzyme in glycolysis in inflammatory macrophages (M1 phenotype). Lactate dehydrogenase B (LDHB) can regulate the NF-κB signaling pathway through the mitochondrial autophagy pathway to facilitate viral replication. LDHB negatively regulates classical swine fever virus (CSFV) growth, whereas CSFV infection inhibits LDHB production and reconstructs the glycolytic metabolic pathway in immune cells by the NS3 protein (46, 47). Interestingly, LDHA expression restricts viral protein synthesis in the ARV-infected cells, whereas the avian reovirus (ARV) σA protein inhibits LDHA expression and upregulates HIF-1α and glycolytic enzymes to promote glycolysis level, thereby favoring viral replication (48). Furthermore, LDH can increase interferon gamma (IFN-γ) expression by promoting histone acetylation (49). Reportedly, glucose consumption is restricted by the inhibition of LDH in CD4⁺ T cells, thus reducing the production of acetyl-CoA, which leads to insufficient histone acetylation modification and reduced IFN-γ production (49). However, the effect of LDH on histone acetylation during virus replication remains largely unknown, and requires further investigation.

Hexosamine, a key metabolite linking glucose metabolism and immunity, activates inflammasomes, innate immune signaling pathways and autophagy. N-acetylglucosamine transferase (OGT) is a critical enzyme in the hexosamine pathway that mediates the glycosylation of target proteins with UDP-GlcNAc to regulate host antiviral immunity and influence viral infections. Hexosamine can induce activation of the inflammatory response and inflammatory cytokine expression through crosstalk between the hexosamine biosynthetic pathway and O-GlcNAc protein modification (50). OGT overexpression promotes O-GlcNAc modification of thioredoxin interacting protein (TxNIP) to facilitate the interaction between TxNIP and NLRP3, which promotes IL-1β production in HEK293T or INS1 832/13 cells (51). OGT is important for NLRP3 activation; however, its activation during viral infections remain largely unknown and requires further investigation. Alternatively, innate immunity can be activated by O-GlcNAc protein modification to regulate viral infection, such as influenza A virus (IAV) and Vesicular stomatitis virus (VSV) (52). A previous study showed that supplementation with D-glucosamine increases O-GlcNAc modification of MAVS to inhibit viral replication, which protects mice against IAV or vesicular stomatitis virus (VSV) challenge (52). During IAV infection, OGT mediates the O-GlcNAcylation of IFN regulatory factor 5 (IRF5) on serine-430, and IAV utilizes the hexosamine pathway to increase the expression of proinflammatory cytokines by stimulating IRF5 leading to in tissue injury (50). VSV infection can enhance HBP activity and O-GlcNAcylation of the downstream protein MAVS at S366, which leads to ubiquitination of the K63 link of MAVS to activate downstream antiviral signals in macrophages (53). Hexosamine can also activate the autophagy pathway to regulate viral infections, a catabolic process that is essential for maintaining cellular homeostasis. It has been shown that low-levels glucose cause decreases in UDP-GlcNAc levels and induce autophagy via the AMPK-Akt/mTOR signaling in the HBV-infected cells (54). Low-level hexosamine can promote HBV replication by inducing autophagosome formation and inhibiting autophagic degradation in vitro and in vivo (54, 55). In addition, low-dose glucosamine treatment promotes the replication of IAV, enterovirus 71 (EV 71), and VSV in vitro (55). O-GlcNAc modification can regulate iron death through iron autophagy and mitochondrial autophagy (56). SNAP-29 is one of the components of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that promotes autophagic vesicle maturation. A recent study revealed that OGT-mediated SNAP-29 O-GlcNAc modification in nematode-infected mammalian cells facilities the activation of autophagy, suggesting that OGT could indirectly promote the maturation of autophagic vesicles in cells (57) ( Table 2 ).

HIF-1α regulates the gene transcription of key enzymes (GLUT1, PKM2, LDHA etc.) ( Figure 1 ) in the glycolytic pathway, which is involved in the modulation of immune responses. Due to its major role in the regulation of glycolysis, HIF-1α can be targeted and hijacked by viruses for viral infections. A recent study has shown that Newcastle disease virus (NDV) infection results in the inhibition of TCA cycle flux and an increase in EMP flux through stable expression of HIF-1α, indicating a shift in energy metabolism from OXPHOS to EMP, which promotes the viral replication, indicating that NDV infection induces mitochondrial damage and hijacks cellular metabolism to promote a shift toward glycolysis to favor viral replication (58). Additionally, under hypoxic conditions, the Kaposi’s sarcoma-associated herpesvirus (KSHV) vGPCR protein induces stable expression of the HIF-1α protein, which leads to metabolic Warburg phenotypic changes associated with KSHV and promotes viral replication in the KSHV-infected PBMCs (18). SARS-CoV-2 infection triggers mitochondrial reactive oxygen species (ROS) production, which stabilizes HIF-1α and promotes glycolysis, thereby contributing to SARS-CoV-2 infection and cytokine production in SARS-CoV-2-infected monocytes and macrophages (59, 60). Therefore, this broad-spectrum effect of HIF-1α on viruses reveals its importance. Moreover, HIF-1α regulates Th9 cell differentiation and exerts antitumor functions. TGF-β1 and IL-4 promote naive CD4⁺ T cells to differentiate into immunoregulatory IL-9-producing helper T (Th9) cells and induce EGFR expression in the EGFR-HIF-1α pathway. EGFR is activated upon binding to the ligand double-regulated protein (AREG), which triggers downstream signaling via HIF-1α and activates the IL-9 and NOS2 promoters, facilitating IL-9 production (61). Notably, HIF-1α is a transcriptional repressor of IRF5 and IRF3 (62), which inhibits the production of type I IFNs. For example, SARS-CoV-2 infection triggers an inflammatory cascade, leading to elevated HMGB1 levels that inhibit IRF5-mediated type I IFN production under hypoxic conditions, only through the NF-κB signaling pathway to trigger monocytes to produce inflammatory cytokines. High mobility group box 1 (HMGB1) can activate NF-κB, IRF3 and IRF5 to release proinflammatory cytokines and I-IFN under normoxia, but SARS-CoV-2 infection can enhance HIF-1α expression, which inhibits IRF3 and IRF5 activity, leading to severe disease in COVID-19 patients (62). HIF-1α is a key activator of inflammatory responses in the SARS-CoV-2-infected PBMCs. HIF-1α expression is correlated with immune-inflammatory cytokine production. SARS-CoV-2-encoded ORF3a induces mitochondrial damage and mitochondrial-ROS production, thus promoting the stable expression of HIF-1α and resulting in cytokine production to enhance the inflammatory response, which is also observed in the VSV or SV-1 infection (58). In particular, HIF-1α is regulated by glycolytic metabolites and further stabilized by succinate and nitric oxide (NO) (61). α-Ketoglutarate (α-KG), a TCA cycle metabolite, is regulated by HIF-1α in Th9 cells. α-KG negatively regulates the stability of HIF-1α. Succinate increases the stability of HIF-1α by impairing prolyl hydroxylase 2 (PHD2) activity, thereby enhancing the antitumor activities of Th9 cells and macrophages (61, 63). HIF-1α can also promote programmed death ligand 1 (PD-L1) expression (64) to inhibit T-cell activation and promote immunoevasion in tumor cells. The high-risk human papilloma virus (HR-HPV) E1/E6 increases HIF-1α levels in cervical cell lines, thereby enhancing the Warburg effect (65–67).

Lactate is an end product of the glycolytic pathway. Lactate can promote the conversion of macrophages to M2 macrophages by modifying histones and regulating polarization-related genes (68), lactate promotes the formation of immunosuppressive M2 macrophages via the induction of arginase differentiation after lactate uptake by macrophages. In addition to modifying histones, lactate regulates viral immunoevasion through innate immune signaling pathways. MAVS is the protein downstream of RIG-I and is involved in crosstalk between the antiviral immune signaling pathways and glycolytic metabolic pathways. Basically, MAVS links energy metabolism and innate immunity through the recognition of lactate (69). Inactivation of glycolysis is essential for the promotion of RLR-mediated type I IFN production. Upon activation of RLR signaling, activated RIG-I “traps” MAVS through the CARD domain to activate downstream molecules and produce IFNs. Then, the oligomerized MAVS dissociates from HK2, which results in a reduction of HK activity, which in turn leads to the inhibition of glycolysis (33). Remarkably, viral infections promote glycolysis, and excess lactate inhibits MAVS and type I IFN production by binding to the transmembrane (TM) domain of MAVS directly and preventing its aggregation. The increased lactate levels in the ASFV-infected porcine alveolar macrophages (PAMs) can inhibit IFN-β production via the RIG-I-MAVS signaling pathway, which can contribute to viral immunoevasion (70). HBV inhibits RLR signaling via the LDHA-dependent lactate production (44). Similarly, LDHA-dependent lactate promotes IAV replication by inhibiting the MAVS-dependent type I IFN response (71). However, LDHA-dependent lactate inhibits SARS-CoV-2 replication (71). There exists interplay between lactate and innate immune responses, indicating that lactate could act as an antiviral target.

Itaconate, a derivative of the TCA cycle citrate, exhibits anti-inflammatory effects and is closely associated with the cGAS-STING signaling pathway (9). A recent study showed that the cell-permeable derivative of itaconate (4-octyl-itaconate, 4-OI) inhibits IL-1β transcription by activating the transcription factor Nrf2, which acts as a transcriptional repressor of IL-1β (72). Inhibition of STING expression is observed during metabolic reprogramming of TLR signaling, and it can also be induced by the TCA cycle via the activation of Nrf2. 4-OI, a cell-permeable derivative of the metabolite oxalic acid, can activate Nrf2 to induce an IFN-independent antiviral program, thereby inhibiting viral replication and suppressing inflammatory responses induced by SARS-CoV-2 infection (72). Furthermore, it has been reported that treatment with Nrf2-inducing agents, such as 4-OI, can sufficiently reduce the STING-dependent type I IFN release in the SAVI-derived fibroblasts, reducing the STING-associated inflammatory disease (9).

Succinate is a TCA cycle intermediate that contributes to the inflammatory response or apoptosis through stabilization of HIF-1α expression or succinylation of proteins (73). It has been shown that succinate can stabilize HIF-1α expression and then induce the expression of IL-1β ( Figure 1 ). Succinate is an endogenous danger signal that stabilizes HIF-1α, which specifically regulates the expression of IL-1β and other HIF-1α-dependent genes, leading to protein succinylation and playing an important role in cell apoptosis or tumor proliferation (63, 74). Succinate promotes HIF-1α stabilization by inhibiting PHD2 activity in macrophages. Succinate can induce the expression of IL-9, HIF-1α and Th9-related genes in Th9 cells, and the induction of Th9 cell differentiation by succinate may occur via inhibiting PHD2 and promoting HIF-1α activity; therefore, succinate treatment enhances the antitumor activity of Th9 cells (61). Succinate is oxidized by succinate dehydrogenase to produce fumarate. Fumarate and its derivatives monomethyl fumarate (MMF) and dimethyl fumarate (DMF) are potent immunomodulators and antioxidants that can activate Nrf2 and modulate oxidative stress in cells, which can suppress HIV replication (75). The Nrf2 agonist DMF significantly inhibits SARS-CoV-2 replication and the expression of inflammatory genes (72). This inhibitory effect has also been observed in infection with viruses, such as herpes simplex virus 1 and 2 (HSV-1 and -2), vaccinia virus (VACV), or Zika virus (ZIKV), indicating that Nrf2 exhibits the extensive antiviral activities (72).

The enzymes associated with the fatty acid biosynthesis pathway not only meet the requirements of the viral life cycle but also participate in the antiviral response. Reportedly, deletion of the fatty acid synthesis-related genes SCD2 and ACC results in reduced production of monounsaturated fatty acids (MUFAs), leading to the activation of the cGAS-STING pathway-mediated interferon-stimulated gene (ISG) expression due to the spontaneous production of IFN-α by CD4⁺ T cells, thereby increasing the antiviral activities of IAV (81). Furthermore, a negative feedback regulatory pathway between STING and FADS2/SCD1 fine-tunes the generation of polyunsaturated fatty acids (PUFAs) associated with inflammatory response, which in turn suppresses the STING-related inflammatory response (82).

The members of the SREBP family modulate the T-cell metabolism and the gene transcription of immune-associated molecules. CD8⁺ T cells with deficient SREBP activity are unable to undergo metabolic reprogramming and blastogenesis, which results in the inability to generate a functional T-cell response (83). Furthermore, the SREBP1c isoform is involved in Th17 cell differentiation and binds directly to the IL-17 promoter to suppress the AhR-induced IL-17 expression in CD4⁺ T cells (84). In addition, the SREBP1a isoform is required for myeloid cells to exert proinflammatory effects, including the secretion of IL-1β, which promotes the expression of NLRP1, a key component of the inflammasome (85). Notably, SREBP1a is required for macrophages to exert proinflammatory effects, including secretion of IL-1β and the expression of NLRP1 (a key component of the inflammasome) (85) ( Figure 2 ).

NF-κB inhibition induced by the peroxisome proliferator-activated receptor gamma (PPAR-γ) activation is the major reason for virus hijacking of fatty acid metabolism to trigger immunoevasion (86). PPAR-γ activation inhibits HIV genomic LTR promoter activity and suppresses the NF-κB response, thereby reducing NF-κB occupancy of the LTR promoter in the infected cells and ultimately impairing HIV replication in macrophages (87). Although both the HIV and HCMV genomes contain elements responsive to NF-κB, the major immediate early promoter (MIEP) contains two PPAR response elements (PPRE) in the HCMV-infected cells. In fact, PPAR-γ promotes viral replication through transactivation of the HCMV promoter MIEP by two PPREs in the HCMV-infected cells (88). The increased activity of PPAR-γ may promote both viral replication and host cell survival. Overexpression of PPAR-γ promotes IAV replication by inhibiting IFN signaling in alveolar macrophages (89).

Apolipoprotein E (ApoE) is linked to a variety of immune responses, including the suppression of T-cell proliferation, the modulation of macrophage function, lipid antigen transport to natural killer T cells, and the regulation of inflammation or oxidation. Proinflammatory cytokines induce the downregulation of ApoE in monocytes. However, TGF-β promotes the expression of ApoE. In addition, ApoE is required for lipoprotein transport. ApoE is known to promote the entry, assembly, and transmission of hepatitis C virus (HCV) (90–92). ApoE has been shown to modulate IAV infection in vitro and in vivo, and ApoE knockout markedly increases the susceptibility of mice to IAV. Notably, when cells are unable to synthesize ApoE, cell cholesterol homeostasis is disrupted to promote IAV attachment (93).

Cholesterol 25-hydroxylase (CH25H) is the key enzyme that regulates cholesterol metabolism and catalyzes the conversion of cholesterol to a soluble, broad-spectrum antiviral effector (25-hydroxycholesterol (25HC)) by adding a second hydroxyl group at position 25 (94). Interestingly, CH25H as an antiviral ISG, forms a part of the sterol metabolic network through interferon signaling (95, 96). It has been shown that CH25H activity is induced by the STAT1-dependent proinflammatory factor IL-1β/TNF-α/IL-6 in the ZIKV-infected cells (96). In addition, 25HC can inhibit virus-induced intercellular membrane fusion and viral infections. ZIKV infection can markedly increase the expression levels of CH25H in cells, thus augmenting the production of 25HC to prevent the virus entry by blocking virus-mediated membrane fusion between cells (97). Interestingly, 25HC can activate an acyl coenzyme A-cholesterol acyltransferase (ACAT) in the endoplasmic reticulum (ER) of cells, which subsequently eliminates accessible cholesterol from the cell membrane, thereby inhibiting viral entry. SARS-CoV-2 initially binds to human lung cells via the ACE2 receptor, and cholesterol in the cellular membrane is required for the membrane fusion of the virus (94). CSFV infection same as well (98) Therefore, 25HC can inhibit the virus entry. Notably, 25HC and 27HC not only inhibit viral entry but also induce the production of proinflammatory cytokines and suppress viral immune evasion. It has been demonstrated that the stimulation of oxysterols enhances HSV-1-induced IL-6 production, indicating that IL-6 exerts antiviral effects during HSV-1 infection, which is an additional antiviral mechanism of action for 25HC and 27HC (99).

Cholesterol is involved in the immunoevasion of viruses. High-levels cholesterol can weaken the host’s antiviral immunity. The PRRSV Nsp4 protein upregulates protein phosphatase 2 (PP2) activity, which activates the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase HMGCR in the cholesterol synthesis pathway and increases cellular cholesterol levels, thereby inhibiting virus-induced IFN-β production and promoting PRRSV replication (100). CSFV infection modulates the cholesterol biosynthesis pathway to favor the virus entry and disrupt the type I IFN response (101, 102). On the contrary, low-levels cholesterol may enhance antiviral immunity in host cells. However, a reduction in cholesterol biosynthesis also enhances host antiviral immunity. When cholesterol synthesis is decreased, STING, a critical antiviral signaling protein, is stimulated to generate antiviral responses. STING appears to require a cholesterol-deficient ER membrane to promote type I IFN production (103) ( Figure 2 ). In summary, CH25H is a molecule with broad spectrum antiviral activity.

SREBP2 is involved in cholesterol metabolism. The maturation of SREBP2, a master transcription factor for cholesterol metabolism, regulates NLRP3 inflammasome activation through the translocation of the SCAP-SREBP2 complex from the ER into the Golgi, thus promoting the activation of the NLRP3 inflammasome. NLRP3 has been reported to form ternary complexes with the SREBP cleavage-activating proteins SCAP and SREBP2, which in turn translocate proximally to the Golgi apparatus to form mitochondrial clusters for efficient assembly of the inflammasome (104).

Glutamine is critical for viral replication, and viral infection regulates the metabolism of glutamine depending on glucose levels. Several viruses transfer carbon to biosynthetic reactions via aerobic glycolysis, using glutamine to replenish intermediates of the TCA cycle, and then reprogramming cellular metabolism to provide the energy required for viral replication and the molecular material for the production of progeny virus. For example, in the VACV-infected HeLa or 2FTGH cells, HIF-1α mediates the shift from glucose to glutamine metabolism via the viral C16 protein, and stimulation of the viral protein contributes to glutamine metabolism to produce α-ketoglutarate and some of the macromolecular precursors of TCA cycle metabolism, which is dependent on glutamine, and asparagine, in the absence of glutamine to promote the production of VACV proteins (39, 106). In the HIV-infected CD4⁺ T cells, the carbon generated from glutamine catabolism enters the TCA cycle to facilitate HIV infection, which is also necessary for maintaining the balance between the TCA cycle and oxidative phosphorylation (107). It has also been shown that glutaminase: kidney-type glutaminase (KGA), glutaminase C (GAC), phosphoribosyl pyrophosphate aminotransferase (PPAT) (key enzymes for de novo purine nucleotide synthesis) and glutamine-fructose-6-phosphate transaminase 1 (a key enzyme in the hexosamine pathway) are significantly differentially expressed after glucose deprivation in the HIV-infected CD4⁺ T cells (35), indicating that the utilization of the glutamine metabolic pathway significantly promotes HIV replication. Glutamine is essential for RGNNV replication as it is converted to α-KG by the enzyme glutaminase (GLS), which is involved in the TCA cycle, and the process promotes RGNNV replication through the TCA cycle (108). HCMV infection increases the glutamine catabolism, which produces α-KG to replenish the TCA cycle and promote HCMV replication (109). In addition, ASFV infection dramatically induces the activation of intracellular glutamine metabolism and facilitates the viral replication in alveolar mononuclear macrophages (27). Furthermore, EV 71 infection can be promoted by increasing glutamine catabolism, while pharmacological inhibition of pyrimidine metabolizing enzymes can inhibit viral replication in Vero cells (110).

Glutamine produces glutamate and glutathione, an antioxidant compound that plays an important role in the prevention of oxidative stress. Similarly, HCV infection increases the utilization and dependence on glutamine, whereas inhibition of glutamine metabolism attenuates the viral infection and the cellular oxidative stress (111). The expression of Myc, two transporter proteins (SLC1A5 and SLC7A5) and two GLSs (KGA and GAC) was increased in the HCV-infected Huh7.5 cells ( Figure 3 ). Myc is a transcription factor that induces the transcription of transporter proteins, thereby driving increased cellular glutamine utilization and thus metabolic reprogramming of cells. Inhibition of glutamine metabolism reduces viral replication and oxidative stress induced by HCV infection, suggesting that the inhibition of glutamine utilization is a novel strategy for the treatment or prevention of viral infection (111).

Glutamine metabolism plays a crucial role in regulating antiviral immunity, as evidenced by the inhibition of the viral infections through glutamine degradation. For example, the proliferation of HSV-infected T cells requires the metabolic breakdown of glutamine. Interestingly, glutamine supplementation has been shown to inhibit the reactivation of latent HSV through a mechanism involving enhancement of the IFN-γ-related immune response, which in turn inhibits the activation of the latent virus (112).

SLC1A3 (aspartic acid transporter, GLAST) is a member of the solute family and is significantly upregulated through the P53 and NF-κB pathways in the NDV-infected DF-1 or A549 cells, and SLC1A3 hijacked by NDV promotes glutamate catabolism and viral replication in host cells (113).

Glutamine has been shown to produce glucosamine, which in turn allows the modification of key proteins through acetylation. This modification helps to regulate cytokine production downstream, which can affect the antiviral immune response in host cells. The process of producing glucosamine involves the catalysis of glutamine and fructose-6-phosphate by glutamine fructose-6-phosphate amidotransferase (GFAT), generating glucosamine-6-phosphate. Finally, UDP-GlcNAc induces modification of the O-GlcNAc protein.

The kynurenine pathway is a complex network of enzymatic reactions that metabolizes tryptophan into various downstream metabolites, including kynurenine, quinolinic acid, and picolinic acid. These metabolites are involved in the modulation of immune responses, oxidative stress, and neurotransmitter synthesis. Tryptophan degradation is primarily mediated by the conversion of tryptophan to kynurenine by two different dioxygenases: indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO2); the rate-limiting step in the tryptophan-kynurenine pathway is performed by IDO1. IDO1 is a multifunctional enzyme that typically acts as a negative regulator of inflammatory and immune responses (114, 115). IDO is a critical regulator of acute pulmonary inflammation. IDO deficiency severely exacerbates lung inflammation in mice. Therefore, IFN signaling in the lung parenchyma inhibits idiopathic pneumonia syndrome by promoting IDO expression (116). It has been demonstrated that changes in tryptophan metabolism are associated with IL-6 levels. In the context of viral infection, IFNs can enhance tryptophan metabolism by inducing IDO1 production subsequently leading to alterations in metabolism and inflammation, which ultimately affect viral replication (117, 118). SARS-CoV-2 infection induces metabolic reprogramming of tryptophan toward the kynurenine pathway, which regulates host inflammation and immunity (119). Furthermore, IFN-γ-induced antiviral activity against measles virus can be counteracted by the addition of excess tryptophan (120). In the context of SARS-CoV-2 infection, dysregulation of the kynurenine pathway has been associated with severe disease outcomes, including cytokine storm and respiratory failure.