Review
Copyright ©The Author(s) 2024.
World J Diabetes. Oct 15, 2024; 15(10): 2041-2057
Published online Oct 15, 2024. doi: 10.4239/wjd.v15.i10.2041
Table 1 Associations of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway with diabetes and complications
Types of complications of diabetes
Link to cGAS-STING pathway
Ref.
Diabetic gastroenteropathyActivation of PI3K/AKT/mTOR and AMPK/mTOR signaling pathways leads to apoptosis of gastric smooth muscle cellsZhang et al[26]
Phosphorylation of S2481 site on mTORC2 can promote glucose metabolism in gastrointestinal smooth muscle cellsYan et al[27]
cGAS STING regulates mTORC1 mediated cell apoptosis through TBK1 signalingBodur et al[28]
cGAS STING regulates mTORC1 mediated cell apoptosis through TREX1 signalingHasan et al[29]
cGAS/STING/IRF3/NF-κB/INF pathway participates in mitochondrial autophagy in the stomach and duodenumPuthanmadhom Narayanan et al[32]
Nonalcoholic fatty liver diseaseActivation of the STING signaling pathway enhances hepatic steatosis and inflammatory response, exacerbating hepatic stellate cell fibrosisWang et al[48], Yu et al[49]
STING promotes macrophage induced liver cell fat deposition and pro-inflammatory response through the NFB and JNK pathwaysLuo et al[47]
STING and IRF3 activation promote lipid accumulation in stem cellsQiao et al[50]
Mitochondrial autophagy mediated mtDNA/cGAS/STING signaling plays a broad regulatory mechanism in different aseptic inflammatory responsesSu et al[51]
Pink1 can inhibit cGAS/STING activation and reduce mitochondrial autophagyZhong et al[52]
Diabetic cardiomyopathyThe use of STING inhibitors in both the lipotoxic H9C2 cell model and the DCM mouse model can significantly inhibit myocardial cell inflammation and apoptosisMa et al[54]
cGAS/STING pathway initiates NLRP3 inflammasome induced cardiomyocyte pyroptosis and chronic inflammationYan et al[55]
cGAS/STING signaling activates the autophagy pathway LKB1/AMPK/ULK1 in cardiomyocytes, leading to hypertrophy, apoptosis, and oxidative damage in primary neonatal rat cardiomyocytes. The cardiac specific overexpression of Metrnl can improve the cardiac injury in diabetes miceLu et al[56]
MtDNA activates the cGAS STING pathway, promoting epithelial mesenchymal transition in vascular endotheliumLiu et al[58]
cGAS exacerbates the inflammatory cascade and participates in the formation of atherosclerosis through the synergistic signaling of IRF and IFNLu et al[59], Pham et al[60]
TDP43 serves as an upstream regulatory factor in AS, triggering inflammatory responses by inducing the release of mtDNA and activating the cGAS STING pathwayHuangfu et al[61]
Diabetes nephropathyThe cGAS STING signaling pathway of renal macrophages is activated, and macrophages are activated towards M1 type through NF-κB signaling protein leads to TNF-α and IL-1β release increaseHan et al[67]
Damage to autophagy in podocytes leads to the accumulation of damaged mitochondria, and TBK1 is an important downstream molecule of the cGAS-STING pathway in podocytesZang[68], Myakala et al[69]
Sacubitril/valsartan can repair mtDNA damage, inhibit cGAS/STING pathway activation, and protect renal functionMyakala et al[70]
DsbA-L can antagonize cGAS/STING pathway activation and improve high glucose induced renal tubular injuryYang et al[71]
Diabetic retinopathyThe levels of STING and p-TBK1 protein in retinal endothelial cells of diabetes mice were significantly increasedWen et al[74]
STING influences PPAR by α plays a key role in the degeneration of retinal glial cells and vascular damageYuan et al[75], Dong et al[79]
TGR5 blocks the IP3R1-GRP75-VDAC1 axis mediated efflux of Ca2+ from the endoplasmic reticulum to mitochondriaLi et al[76]
Upregulation of ARPE-19 gene expression and STIGN-NF-κB pathway activation relatedChen et al[77]
JQ-1cGAS-STING inhibitor can alleviate retinopathy caused by oxidative stress in diabetesZou et al[78]
Diabetic woundROS induces macrophage polarization through mtDNA/STING signaling, exacerbating endothelial cell dysfunctionGeng et al[81]
STING inhibitors can inhibit inflammation and promote wound healingFeng et al[82]
IRF3 regulates Hippo YAP pathway to inhibit wound healingYuan et al[83]
STING leads to an increase in JMJD3 in macrophages, limiting wound repair and enhancing inflammatory responseAudu et al[84]
Table 2 Mechanistic and physiologic effects of cyclic guanosine monophosphate-adenosine monophosphate synthase inhibitors associated with diabetes and its complications
Inhibitor
Mechanism
Physiologic effects
Compound 18Small molecule inhibitors break the molecular structure of cGAS by binding to hydrogen bonds[91]Compound 18 improves glucose tolerance in high fat diet mice[94]
RU.521, RU.356, RU332Competes with ATP and GTP for enzyme binding sites by virtue of its own structural advantages[95]RU521 attenuates cGAS-STING-mediated cardiac dysfunction in BRG1 knockout diabetic cardiac mice[96]
PF-06928215Competes with cGMP for the cGAS binding site[97]PF-06928215 attenuates cGAS-STING-mediated cardiac dysfunction in double knockout of Akt2 and AMPK mice[98]
HCQPrevents cGAS from binding to DNA by occupying the DNA binding site[97]Improvement of inflammation by decreasing IFN-β release from Th1 cells
AspirinAspirin acetylates cGAS to block cGAS-STING signaling. Aspirin’s metabolite salicylate may affect NF-κB nuclear translocation[89]No relevant evidence. Aspirin is only a theoretical cGAS inhibitor because it is easily hydrolyzed in the body
SuraminSimilar to nucleic acid structure, competes for DNA and cGAS binding sites[99]Suramin blocks dsDNA binding to cGAS and limit AIM2 inflammatory vesicle formation[100]
Table 3 Mechanistic and physiologic effects of stimulator of interferon gene inhibitors associated with diabetes and its complications
Inhibitor
Mechanism
Physiologic effects
Nitro fatty acidsInhibits palmitoylation by binding to STING[101]Nitro fatty acids protect against mitochondrial damage in hepatocytes of mice with nonalcoholic fatty liver disease[102]
C-176Covalent small molecule inhibitors. Inhibits STING palmitoylation[103]C-176 attenuates cGAS-STING pathway-mediated diabetic cardiomyopathy[54]
UNC93B1The mechanism of action involves the targeting of STING degradation via the autophagy-lysosome pathway[104]Unc93b1 ameliorates neuronal apoptosis induced by high glucose through the TLR9 signaling pathway[105]
SP23Hydrolysis STING by the ubiquitin-proteasome pathway[106]Improvement of inflammation by decreasing IFN-β release from Th1 cells