Fig. 6

The relationship between STING and metabolism. a Nucleic acid and lipid metabolism and STING. Imbalanced cytosolic nucleotide pools can trigger the mitochondrial stress and mtDNA release via VDAC, which activates the cGAS–STING pathway. Interestingly, STING-mediated TBK1 activation can also promote PRPP synthesis by activating the PRPSs. The activated IRF3 dimer enters the nucleus and induces transcription of interferon and ISGs like ISG15. IFN can act in an autocrine way and induce metabolic reprogramming. ISG15 is reported to inhibit glycolysis by covalently modifying the multiple key enzymes. STING activation in tumor cells can induce a decline of NAD⁺ with the known mechanism. b Redox balance and STING. Direct delivery of oxidants such as hydrogen peroxide, hypochlorous acid, diamide, and respiratory chain-based ROS inducers such as rotenone, menadione can induce overwhelming ROS can dampen the STING activation. The intracellular antioxidant system GPX4 can maintain the redox balance and normal STING activation. In addition, NRF2 negatively regulates STING expression by decreasing STING mRNA stability. Oxidative stress activates FOXO3 and its transcriptional target GNMT. Reduced intracellular SAM availability induced cytosolic release of chromatin fragments and subsequent cGAS-STING activation via disrupting carboxymethylation and maturation of nuclear lamin. A2B1: hnRNPA2B1A; CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, DHODH dihydroorotate dehydrogenase, DNMT1 DNA methyltransferase 1, DsbA-L disulfide bond A oxidoreductase-like protein, DUBs deubiquitinating enzymes, ER endoplasmic reticulum, FTO fat mass and obesity-associated gene, GPX4 glutathione peroxidase 4, G6P Glucose 6-phosphate, GNMT glycine-N-methyltransferase, HK hexokinase, IFNβ interferon beta, IRF3 interferon regulatory factor 3, ISG interferon-induced genes, Met methionine, METTL3 methyltransferase-like 3, m6A N6-methyladenosine, MUFAs monounsaturated fatty acids, H-Cys homocysteine, H3K27me3 trimethylation of lysine-27 in histone 3, NAD+ nicotinamide adenine dinucleotide, NRF2 nuclear factor erythroid 2-related factor 2, PPP pentose phosphate pathway, PRPP phosphoribosyl pyrophosphate, PRPSs phosphoribosyl pyrophosphate synthetases, ROS reactive oxygen species, R5P ribose 5-phosphate, SAH S-adenosylhomocysteine, SAM S-adenosylmethionine, SREBP2 sterol-regulatory element binding protein 2, SCAP SREBP-cleavage activating protein, STING stimulator of interferon genes, TBK1 TANK-binding kinase 1, TFAM mitochondrial mtDNA-binding protein transcription actor A, TYMS thymidylate synthetase, PAPS 3’-phosphoadenosine-5’-phosphosulfate, PUFAs polyunsaturated fatty acids, VDAC voltage-dependent anion channel