Aug 2026· Archives of pharmacal research· Vol 49, pp. 1032 - 1052· 0 citations· 140 references
Medicine
TL;DR
Evidence linking dysregulated cGAS–STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction is synthesized, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs.
The mechanisms of cGAS-STING activation in aging-including mitochondrial DNA leakage, nuclear envelope disruption, and retrotransposon activation-and its role in driving cellular senescence and the senescence-associated secretory phenotype (SASP) are reviewed.
Yutong Wei, Sutong Cai, Yanan Ji et al.· Biochemical Pharmacology· 2 citations
Aging and its associated diseases have become an increasingly severe global health challenge, not only significantly exacerbating the global disease burden but also posing a continuous threat to public health systems worldwide. During the aging process, the aberrant release of endogenous mitochondrial DNA (mtDNA) is a key trigger for the activation of the cGAS–STING innate immune pathway. Existing research has confirmed that the overactivation of the cGAS–STING pathway is the core molecular mechanism driving the senescence-associated secretory phenotype (SASP), chronic inflammation, and organ functional decline. Notably, the mechanisms of mtDNA release and the activation characteristics of the cGAS–STING pathway exhibit significant organ-specificity. Different tissues mediate mtDNA leakage through specific pathways, such as mitochondrial permeability transition, oxidative damage, and defective mitophagy, thereby differentially regulating downstream inflammatory signals. Given the central driving role of the aberrantly activated mtDNA-cGAS-STING axis in age-related organ damage, targeting this pathway has emerged as a promising therapeutic strategy for the systemic mitigation of aging-associated chronic inflammation. This review systematically elucidates the molecular basis of the mtDNA-cGAS-STING pathway, delves into its organ-specific activation mechanisms, and critically evaluates current intervention frameworks and clinical prospects, aiming to provide a theoretical basis and innovative perspectives for the precision prevention and clinical management of age-related diseases.
Ling Wang, Zhengwei Zhang, Bin-Bin Xia et al.· Frontiers in Immunology· 0 citations
How context determines the consequences of cGAS/STING activation in cancer is examined, emerging therapeutic strategies that modulate this pathway are reviewed, and how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation is discussed.
Yi Wang, J. Angulo-Lozano, Yue-Qi Wang et al.· Journal of Clinical Investig...· 0 citations
This review synthesizes current research on how intracellular C3 (intC3), and intracellular C5 (intC5) in certain contexts engage in extensive crosstalk with the mTOR, NF-κB, and AMPK pathways to modulate core cellular processes to modulate age-related diseases.
Naheemat Modupeola Gold, M. N. Okeke, Samuel Ewhea Ajoronor et al.· Ageing Research Reviews· 0 citations
Diabetes mellitus and its complications represent a major global public health challenge, with their pathogenesis closely linked to chronic, low-grade, non-infectious metabolic inflammation. The cGAS-STING signaling pathway, a crucial innate immune sensor of cytosolic DNA, has recently emerged as a central hub linking metabolic stress to sterile inflammation. This review systematically elucidates the mechanisms and therapeutic potential of the cGAS-STING pathway in diabetes mellitus and its associated complications. Under diabetic metabolic stress conditions—such as hyperglycemia and lipotoxicity—mitochondrial dysfunction and nuclear DNA damage lead to the leakage of DNA into the cytoplasm, which acts as damage-associated molecular patterns (DAMPs) to activate the cGAS-STING pathway. Aberrant activation of this pathway is extensively involved in the pathogenesis of various diabetic complications, including diabetic cardiomyopathy (DCM), nephropathy, retinopathy, foot ulcers, and macrovascular disease, driving tissue damage through mechanisms such as pyroptosis, inflammatory responses, fibrosis, and cellular senescence. Furthermore, the cGAS-STING signaling cascade plays a critical role in core pathological processes of diabetes mellitus, including the regulation of insulin resistance, adipose tissue inflammation, and pancreatic β-cell dysfunction. Current intervention strategies targeting this pathway—comprising small molecule inhibitors (e.g., STING inhibitors C-176/H-151, cGAS inhibitor RU.521), strategies for mitochondrial quality control (e.g., modulating mitophagy and mitochondrial dynamics), and various natural products and traditional Chinese medicine formulations—have demonstrated significant therapeutic promise in preclinical models. Nevertheless, challenges remain in this field, including cell-type specificity, therapeutic windows, pathway redundancy, and a lack of reliable biomarkers. Future directions aimed at advancing targeted therapies of the cGAS-STING pathway from bench to bedside should focus on leveraging single-cell multi-omics technologies to decipher its spatiotemporal specificity, developing precision-targeted delivery systems, exploring multi-target combination strategies, and establishing clinically applicable biomarkers. This review provides a novel perspective on the inflammatory mechanisms underlying diabetes mellitus and its complications, thereby establishing a theoretical foundation for the development of therapeutic strategies centered on modulating the cGAS-STING pathway.
Guang-Dong Qi, Tong-Xin Shang, Hua-Lin Sun et al.· Frontiers in Pharmacology· 0 citations
How the delicate balance between acute and chronic STING signaling in the setting of underlying genetic regulation and immune landscape can play critical role in determining clinical outcome is discussed.
Satyaki Bhowmik, Subhadeep Ghosh, A. Sengupta· Experimental Hematology· 0 citations
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