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Emerging preclinical evidence identifies the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS\u2013STING) pathway as a critical mediator of diabetic cardiovascular inflammation. Metabolic stressors in T2DM\u2014hyperglycemia, lipotoxicity, and mitochondrial dysfunction\u2014induce leakage of mitochondrial and microbial double-stranded DNA into the cytosol, where it engages cGAS and activates STING. Subsequent TBK1\/IRF3 and NF-\u03baB signaling drives low-grade inflammation across cardiomyocytes, endothelial cells, macrophages, and fibroblasts. Genetic deletion of cGAS or STING in high-fat-diet-fed diabetic mice reduces NLRP3 inflammasome-mediated pyroptosis, limits atherosclerotic lesion formation, and preserves cardiac contractile performance. Pharmacological inhibitors, including RU.521 (cGAS antagonist), C-176\/H-151 (STING palmitoylation blockers), and the TBK1 inhibitor amlexanox, effectively lower pro-inflammatory cytokines (IL-1\u03b2, IL-6, TNF-\u03b1) and improve left ventricular ejection fraction in diabetic cardiomyopathy and ischemia\u2013reperfusion injury models. Novel PROTAC degraders targeting cGAS\/STING and natural products such as Astragaloside IV and Tanshinone IIA further support the pathway\u2019s druggability. Collectively, these findings position the cGAS\u2013STING axis as a central molecular nexus linking metabolic derangement to cardiovascular pathology in T2DM and underscore its inhibition or targeted degradation as a promising dual cardiometabolic therapeutic strategy.<\/jats:p>","DOI":"10.3390\/cimb47090750","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:08:16Z","timestamp":1757678896000},"page":"750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights"],"prefix":"10.3390","volume":"47","author":[{"given":"Guida","family":"Cai","sequence":"first","affiliation":[{"name":"Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexi","family":"Jiao","sequence":"additional","affiliation":[{"name":"Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Du","sequence":"additional","affiliation":[{"name":"Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7652-129X","authenticated-orcid":false,"given":"Meiling","family":"Yan","sequence":"additional","affiliation":[{"name":"Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res Clin Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.cmet.2021.07.001","article-title":"Cardiovascular disease in diabetes, beyond glucose","volume":"33","author":"Eckel","year":"2021","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1152\/physrev.00065.2017","article-title":"Innate Immune Signaling and Its Role in Metabolic and Cardiovascular Diseases","volume":"99","author":"Xu","year":"2019","journal-title":"Physiol. 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