cGAS–STING signaling pathway in diabetes: Prospects and challenges

Diabetes mellitus (DM), a metabolic disorder characterized by persistent hyperglycemia and impaired insulin function, has been increasingly linked to inflammatory mechanisms. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway, a central axis mediating inflammatory responses, has been implicated in the pathogenesis of DM. Activation of STING triggers the secretion of various inflammatory mediators and influences critical diabetic processes, such as insulin resistance (IR), pancreatic β-cell dysfunction, and cellular autophagy. This article discusses the role of cGAS–STING in diabetes and explores potential small-molecule inhibitors that target this pathway, thereby offering new therapeutic avenues for DM and its complications. Over the past two decades, chronic inflammation has been found to be an important feature of diabetes, affecting the pancreatic islets and insulin target tissues.[1] Notably, islet inflammation, previously associated with type 1 DM (T1DM), is now recognized in type 2 DM (T2DM). Elevated levels of inflammatory chemokines are associated with IR, giving rise to the concept of “immunometabolism”. The cGAS–STING pathway initiates immune responses by detecting cytosolic DNA. cGAS senses mislocalized double-stranded DNA (dsDNA) and synthesizes cyclic AMP–GMP (cGAMP). Upon cGAMP binding, STING translocates from endoplasmic reticulum (ER) to Golgi apparatus, recruiting TANK-binding kinase 1 (TBK1) to phosphorylate interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), leading to production of type I interferons (IFN-I) and pro-inflammatory factors. Beyond its role in innate immunity, the cGAS–STING pathway regulates β-cell dysfunction, apoptosis, autophagy, and IR in diabetes. Additionally, studies have demonstrated that reduced islet inflammation improves islet function in STING-deficient mice, suggesting a role for this pathway in inflammation in diabetes.[2] cGAS–STING and islet dysfunction: Pancreatic β-cell apoptosis mediated by inflammatory cytokines is a primary trigger of T1DM, with genetic predisposition playing a significant role. PLAGL1, a T1DM susceptibility gene, induces β-cell death via mitochondrial damage and cytoplasmic DNA accumulation, activating the cGAS–STING–IRF3–NF-κB pathway and amplifying IFN-I signaling, which exacerbates β-cell destruction.[3] In T2DM, islet inflammation, lipotoxicity and glucotoxicity, ER stress, especially β-cell compensatory response to IR, all impair β cell survival and function. Under diabetogenic stress, mitochondrial DNA (mtDNA) release activates the cGAS–STING pathway, thereby contributing to T2DM.[4] Recently, Hong et al[5] reported that incubation with palmitic acid (PA) promotes mtDNA release and subsequently activates cGAS–STING signaling in islet macrophages, impairing glucose-stimulated insulin secretion (GSIS), whereas STING inhibition restores insulin secretion and islet function. In addition to its role in immunity, cGAS also affects β-cell proliferation and promotes diabetes. cGAS deficiency boosts β-cell proliferation by reducing the expression of ​CCAAT/enhancer-binding protein β (CEBPβ), a β-cell proliferation suppressor, revealing cGAS’s multifunctional role in diverse cellular processes.[6] To clarify STING’s role in β-cells, Qiao et al[2] reported that global STING deletion ameliorated IR in peripheral insulin target tissues and improved glucose tolerance; however, β-cell–specific STING deletion unexpectedly impaired GSIS and led to glucose intolerance. They further revealed that STING deletion in β-cells decreased the expression and activity of Pax6, a key β-cell transcription factor, thereby downregulating glucose transporter (Glut2), which is critical for β-cell GSIS. These findings underscore the distinct, tissue-specific roles of STING in maintaining glucose homeostasis. cGAS–STING and IR in diabetes: Obesity-associated inflammation, including activation of the cGAS–STING pathway, contributes to the development of IR.[7] Adipose tissue-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L) triggers mtDNA release, cGAS–STING activation, and worsened IR.[7] Mao et al[8] identified STING as a critical mediator of PA-induced endothelial inflammation, while STING deficiency partially prevented diet-induced inflammation, obesity, IR, and glucose intolerance. Downstream TBK1–IRF3 signaling also plays a critical role in inflammation and IR. TBK1 promotes IR by phosphorylating the insulin receptor at Ser residue 994,[9] whereas global TBK1 knockout or its pharmacological inhibition improves insulin sensitivity.[10,11] Similarly, IRF3 ablation in the liver or adipose tissue reduces inflammation, reverses IR, and restores glucose homeostasis.[12] Recently, Chen et al[13] found that Hoxa5, an important transcription factor, alleviates metabolic disturbances and improves IR by inhibiting the cGAS–STING–TBK1–IRF3 pathway, highlighting this pathway as a critical target for regulating glucose homeostasis in obesity. However, TBK1–IRF3 signaling exhibits context-dependent roles. Zhao et al[14] demonstrated that TBK1 deficiency in adipocytes led to increased activation of NF-κB, accompanied by exaggerated IR in high-fat diet-fed mice. The anti-inflammatory effect of TBK1 is mediated by the phosphorylation of NF-κB-inducing kinase (NIK), which results in NIK degradation and reduced activity of the atypical NF-κB pathway. In addition, Wang et al[15] revealed that IRF3 plays a protective role against diet-induced hepatic IR by inhibiting the pro-inflammatory NF-κB pathway and alleviating hepatic inflammation, steatosis, and IR. Collectively, the cGAS–STING–TBK1–IRF3 signaling pathway plays a tissue-specific role in metabolic regulation, and further research is needed to elucidate the metabolic–inflammatory crosstalk. Crosstalk between cGAS–STING and autophagy in diabetes: Autophagy maintains cellular homeostasis. STING triggers LC3 lipidation to form autophagosomes via the WD repeat domain phosphoinositide-interacting protein 2 (WIPI2) and autophagy protein 5 (ATG5), enabling cytosolic DNA clearance. Activated STING undergoes autophagic degradation to prevent excessive inflammation. Impaired autophagy inhibits STING degradation and exacerbates inflammation and IR. Ali et al[16] observed a significant increase in STING expression and a marked decrease in autophagy-associated LC3B expression in the livers and kidneys of animals with T2DM. However, treatment with Rosavin alleviated T2DM symptoms and reduced inflammation by activating autophagy and inhibiting STING signaling in rats with T2DM. Similarly, meteorin-like hormone (Metrnl) treatment ameliorated cardiac injury and dysfunction by activating cytoprotective autophagy and inhibiting cGAS–STING signaling in hyperglycemia-challenged cardiomyocytes.[17] Collectively, these results suggest that autophagy restrains excessive inflammation by suppressing STING aggregation and activation. The cGAS–STING pathway as a target in DM: Several hypoglycemic compounds and plant-derived agents that exert anti-diabetic effects by modulating cGAS–STING to improve metabolic homeostasis are summarized in Supplementary Table 1, https://links.lww.com/CM9/C711, highlighting the therapeutic relevance of this pathway in diabetes management. Besides, several inhibitors targeting cGAS or STING have been shown to suppress inflammatory responses and ameliorate diabetic symptoms in experimental models [Supplementary Table 2, https://links.lww.com/CM9/C711]. Overactivation of the cGAS–STING pathway contributes to the pathogenesis of diabetes and its complications by driving inflammation, IR, and pancreatic islet dysfunction. Therefore, targeting this pathway holds promise for alleviating diabetic symptoms, with cGAS or STING inhibitors shown to reduce inflammation, improve IR, and maintain β-cell function. However, key challenges remain, including classifying the distinct roles of STING in T2DM and elucidating the specific mechanisms underlying cGAS–STING-mediated diabetes pathogenesis. Given the essential role of cGAS–STING in immunity, developing strategies, such as tissue-specific delivery systems or transient inhibition protocols, which selectively inhibit this pathway without compromising host defenses, is critical for clinical translation. Moreover, owing to the anatomical and physiological differences between species, substantial translational challenges exist in moving from bench to bedside. Addressing these issues will advance the development of precise and effective therapeutics for diabetes and other metabolic diseases. Funding This study was supported by the National Natural Sciences Foundation of China (Nos. 82300522 and 82400542), Hunan Provincial Natural Science Foundation of China (No. 2024JJ5347), Hubei Provincial Natural Science Foundation of China (No. 2023AFB043), Health Research Project of Hunan Provincial Health Commission (No. W20243007), The Research Foundation of Education Bureau of Hunan Province (No. 22B0415), Undergraduate Research and Innovation Project of University of South China (No. 2024CX002). Conflicts of interest None.