Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

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 gastroenteropathy	Activation of PI3K/AKT/mTOR and AMPK/mTOR signaling pathways leads to apoptosis of gastric smooth muscle cells	Zhang et al[26]
	Phosphorylation of S2481 site on mTORC2 can promote glucose metabolism in gastrointestinal smooth muscle cells	Yan et al[27]
	cGAS STING regulates mTORC1 mediated cell apoptosis through TBK1 signaling	Bodur et al[28]
	cGAS STING regulates mTORC1 mediated cell apoptosis through TREX1 signaling	Hasan et al[29]
	cGAS/STING/IRF3/NF-κB/INF pathway participates in mitochondrial autophagy in the stomach and duodenum	Puthanmadhom Narayanan et al[32]
Nonalcoholic fatty liver disease	Activation of the STING signaling pathway enhances hepatic steatosis and inflammatory response, exacerbating hepatic stellate cell fibrosis	Wang et al[48], Yu et al[49]
	STING promotes macrophage induced liver cell fat deposition and pro-inflammatory response through the NFB and JNK pathways	Luo et al[47]
	STING and IRF3 activation promote lipid accumulation in stem cells	Qiao et al[50]
	Mitochondrial autophagy mediated mtDNA/cGAS/STING signaling plays a broad regulatory mechanism in different aseptic inflammatory responses	Su et al[51]
	Pink1 can inhibit cGAS/STING activation and reduce mitochondrial autophagy	Zhong et al[52]
Diabetic cardiomyopathy	The use of STING inhibitors in both the lipotoxic H9C2 cell model and the DCM mouse model can significantly inhibit myocardial cell inflammation and apoptosis	Ma et al[54]
	cGAS/STING pathway initiates NLRP3 inflammasome induced cardiomyocyte pyroptosis and chronic inflammation	Yan 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 mice	Lu et al[56]
	MtDNA activates the cGAS STING pathway, promoting epithelial mesenchymal transition in vascular endothelium	Liu et al[58]
	cGAS exacerbates the inflammatory cascade and participates in the formation of atherosclerosis through the synergistic signaling of IRF and IFN	Lu 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 pathway	Huangfu et al[61]
Diabetes nephropathy	The 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 increase	Han 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 podocytes	Zang[68], Myakala et al[69]
	Sacubitril/valsartan can repair mtDNA damage, inhibit cGAS/STING pathway activation, and protect renal function	Myakala et al[70]
	DsbA-L can antagonize cGAS/STING pathway activation and improve high glucose induced renal tubular injury	Yang et al[71]
Diabetic retinopathy	The levels of STING and p-TBK1 protein in retinal endothelial cells of diabetes mice were significantly increased	Wen et al[74]
	STING influences PPAR by α plays a key role in the degeneration of retinal glial cells and vascular damage	Yuan et al[75], Dong et al[79]
	TGR5 blocks the IP3R1-GRP75-VDAC1 axis mediated efflux of Ca2+ from the endoplasmic reticulum to mitochondria	Li et al[76]
	Upregulation of ARPE-19 gene expression and STIGN-NF-κB pathway activation related	Chen et al[77]
	JQ-1cGAS-STING inhibitor can alleviate retinopathy caused by oxidative stress in diabetes	Zou et al[78]
Diabetic wound	ROS induces macrophage polarization through mtDNA/STING signaling, exacerbating endothelial cell dysfunction	Geng et al[81]
	STING inhibitors can inhibit inflammation and promote wound healing	Feng et al[82]
	IRF3 regulates Hippo YAP pathway to inhibit wound healing	Yuan et al[83]
	STING leads to an increase in JMJD3 in macrophages, limiting wound repair and enhancing inflammatory response	Audu et al[84]

cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: Stimulator of interferon gene; PI3K: Phosphatidylinositol 3-kinase; AKT: Activated protein kinase B; mTOR: Mammalian target of rapamycin; mTORC2: Mammalian target of rapamycin complex 2; TBK1: TANK-binding kinase 1; TREX1: 3-prime repair exonuclease 1; IRF3: Interferon regulatory factor 3; NF-κB: Nuclear factor-κB; IFN: Interferon; JNK: c-Jun NH2-terminal kinase; mtDNA: Mitochondrial DNA; NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3; Metrnl: Meteorin-like; AS: Atherosclerosis; TNF: Tumor necrosis factor; IL: Interleukin; PPAR: Peroxisome proliferator-activated receptor; TGR5: Takeda G protein-coupled receptor 5; ROS: Reactive oxygen species; YAP: Yes-associated protein; JMJD3: Jumonji domain-containing protein-3.

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 18	Small 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, RU332	Competes 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-06928215	Competes 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]
HCQ	Prevents cGAS from binding to DNA by occupying the DNA binding site[97]	Improvement of inflammation by decreasing IFN-β release from Th1 cells
Aspirin	Aspirin 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
Suramin	Similar 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]

cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: Stimulator of interferon gene; ATP: Adenosine triphosphate; GTP: Guanosine triphosphate; cGMP: Cyclic guanosine monophosphate; NF-κB: Nuclear factor-κB; Akt: Activated protein kinase B; AMPK: Adenosine monophosphate-activated protein kinase; IFN: Interferon; Th1: T helper type 1; dsDNA: Double-stranded DNA; AIM2: Absent in melanoma 2.

Table 3 Mechanistic and physiologic effects of stimulator of interferon gene inhibitors associated with diabetes and its complications

Inhibitor	Mechanism	Physiologic effects
Nitro fatty acids	Inhibits palmitoylation by binding to STING[101]	Nitro fatty acids protect against mitochondrial damage in hepatocytes of mice with nonalcoholic fatty liver disease[102]
C-176	Covalent small molecule inhibitors. Inhibits STING palmitoylation[103]	C-176 attenuates cGAS-STING pathway-mediated diabetic cardiomyopathy[54]
UNC93B1	The 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]
SP23	Hydrolysis STING by the ubiquitin-proteasome pathway[106]	Improvement of inflammation by decreasing IFN-β release from Th1 cells

cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: Stimulator of interferon gene; IFN: Interferon; Th1: T helper type 1; TLR9: Toll-like receptor 9.