Miriam Ahmed

Background: Diabetic cardiomyopathy (DCM) is a form of dilated cardiomyopathy that initially presents with diastolic dysfunction and left ventricular hypertrophy. In its advanced stages, DCM progresses to systolic dysfunction and myocardial fibrosis.² Currently, there are no targeted therapies for DCM.² Previous studies have shown that hyperglycemic conditions can activate the cGAS–STING pathway through the release of cytosolic mitochondrial DNA, leading to the production of proinflammatory cytokines such as IL-6, IL-1β, and TNF-α.^1,3 Although cGAS–STING activation is recognized as a mediator of inflammation, it has now been proposed in promoting key pathological features of DCM, including cardiac hypertrophy, fibrosis, and pyroptosis. ^5,6,7 These findings suggest that the cGAS–STING pathway may represent a promising therapeutic target for future treatment of DCM.

Research Objectives: In this narrative review, we explore the mechanisms by which cGAS-STING activation and knockout contributes to the pathogenic features that characterize DCM.

Methods: A PubMed search was conducted using the keywords: “Diabetic Cardiomyopathy”, “cGAS-STING”, “inflammation”, “pyroptosis”, and “fibrosis” and focused on literature published since 2019.

Results: Several sequential results emerged from the review. In a mouse model of obesity-induced diabetes, there was increased cytosolic mtDNA and cGAS/STING activation, along with increased levels of downstream cGAS-STING molecules like TNF-α, IL-1β, IL-18.⁵ STING inhibition was also found to partially improve diastolic dysfunction and reduce fibrosis within the mice.⁵ These findings established cGAS-STING immune activation as a central mechanism in DCM pathology.⁵ Another study found that STING knockdown mice had decreased mRNA levels of hypertrophy-related genes like ANP and BNP, and have elevated executioners of pyroptosis markers like NLRP3, caspase-1, and GSDMD.⁶ These data demonstrate downstream functional effects of STING activation in promoting DCM damage via pyroptotic cell death and pathological hypertrophy.⁶ Additionally, studies show DCM induced pyroptosis can be targeted via cGAS-STING downstream pathways in a NLRP3 inflammasome-dependent manner.⁷  In-vitro and in-vivo models of NLRP3 knockdown found increased ATP levels, decreased LDH, and restored mitochondrial function. In vivo models found decreased cardiomyocyte hypertrophy, vacuole-like lesions, mitochondrial disorganization, and decreased GSDMD. Ultimately, NLRP3 knockdown offers an additional downstream therapeutic target in slowing DCM related pyroptosis and improving cell viability.⁷ Several therapeutic agents have been identified to target DCM pathological mechanisms. DICAR, a highly conserved circRNA, is identified to block NLRP3 activation and pyroptosis.⁸ Meteorin-like hormone (Metrnl), a native cardioprotective agent against cardiac hypertrophy, upregulates STING autophagy.⁹ Therefore, DICAR and Metrnl regulate DCM induced hypertrophy and pyroptosis and may serve as future drug treatments.^8,9 Lastly, analysis of serum from 100 individuals with and without DCM demonstrated that cGAS-STING–associated serum biomarkers (ANP, BNP, TNF-α, IL-6) were significantly elevated in individuals with DCM. These findings highlight the potential utility of cGAS-STING–associated serum biomarkers for early detection of cardiac dysfunction in diabetics progressing toward DCM, thereby allowing early treatment to improve prognosis and cardiac decline.^7,10

Conclusions: cGAS-STING has been identified to play a crucial role in DCM.⁵  cGAS-STING inhibition in DCM decreases cardiac dysfunction, partially reverses hypertrophy, pyroptosis, and fibrosis.^5,6,7 Parallel pathways like the NLRP3 inflammasome and agents like DICAR and Metrnl offer targeted therapy. ^8,9 The utility of cGAS-STING-associated serum biomarkers also allow for early detection of DCM before heart failure is irreversible.^7,10

Work Cited:

1.  Nakamura K, Miyoshi T, Yoshida M, et al. Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus. International Journal of Molecular Sciences. 2022;23(7):3587. doi:https://doi.org/10.3390/ijms23073587
2. Paolillo S, Marsico F, Prastaro M, et al. Diabetic Cardiomyopathy. Heart Failure Clinics. 2019;15(3):341-347. doi:https://doi.org/10.1016/j.hfc.2019.02.003
3. Peng M, Fu Y, Wu C, Zhang Y, Ren H, Zhou S. Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy. Frontiers in Endocrinology. 2022;13. doi:https://doi.org/10.3389/fendo.2022.907757
4. Monda E, Palmiero G, Rubino M, et al. Molecular Basis of Inflammation in the Pathogenesis of Cardiomyopathies. International Journal of Molecular Sciences. 2020;21(18):6462. doi:https://doi.org/10.3390/ijms21186462
5. Ma XM, Geng K, Law BY, et al. Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes. Cell Biol Toxicol. 2023;39(1):277-299. doi:10.1007/s10565-021-09692-z
6. Yan M, Li Y, Luo Q, et al. Mitochondrial damage and activation of the cytosolic DNA sensor cGAS-STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice. Cell Death Discov. 2022;8(1):258. Published 2022 May 11. doi:10.1038/s41420-022-01046-w
7. Wang J, Li Y, Li L, et al. Effect of NLRP3 gene knockdown on pyroptosis and ferroptosis in diabetic cardiomyopathy injury. BMC Cardiovasc Disord. 2024;24(1):351. Published 2024 Jul 10. doi:10.1186/s12872-024-04010-x
8. Yuan Q, Sun Y, Yang F, et al. CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes. Signal Transduct Target Ther. 2023;8(1):99. Published 2023 Mar 8. doi:10.1038/s41392-022-01306-2
9. Lu QB, Ding Y, Liu Y, et al. Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy. J Adv Res. 2023;51:161-179. doi:10.1016/j.jare.2022.10.014
10. Abdelrahman AH, Salama II, Salama SI, et al. Role of some serum biomarkers in the early detection of diabetic cardiomyopathy. Future Science OA. 2021;7(5). doi:https://doi.org/10.2144/fsoa-2020-0184
11. Li X, Guo K, Zhou Q, et al. Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice. Life Sciences.2025;366-367:123470. doi:https://doi.org/10.1016/j.lfs.2025.123470