Aug 2026· Biochemical Pharmacology· Vol 253, pp.
118317
· 2 citations· 167 references
Medicine
TL;DR
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.
Abstract
Agingis characterized by chronic low-grade inflammation ("inflammaging"), a key driver of functional decline and age-related diseases. The cGAS-STING pathway, which senses cytosolic DNA, has emerged as a central mediator of this sterile inflammation. Here, we systematically review 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). We examine the pathway's pathological contributions across multiple systems, including the nervous, cardiovascular, musculoskeletal, metabolic, reproductive, and sensory systems. We also discuss therapeutic strategies targeting cGAS-STING, encompassing small-molecule inhibitors, natural products, nanomedicine, and gene therapy. Furthermore, we integrate AlphaFold3-based structural modeling and CB-DOCK2 molecular docking analyses to characterize the binding modes and affinities of key inhibitors (e.g., H-151, RU.521, VBIT-4, Mdivi-1) to cGAS, STING, VDAC1, and DRP1, providing a structural rationale for their therapeutic potential. Finally, we address current challenges, including tissue-specific effects and pathway complexity, and highlight future directions for translating these insights into clinical interventions for aging and age-associated disorders.
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.
Yingying Xu, Weidong Wu, Yifan Guo et al.· Archives of pharmacal resear...· 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
Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying “inflammation–death” cycle. In Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis.
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
This review systematically integrates existing preclinical and early clinical evidence within the framework of "cytokine signaling networks", focusing on elucidating the molecular mechanisms and biological effects of selinexor in suppressing proinflammatory factor production, mitigating oxidative stress, and regulating inflammatory tissue-remodeling networks.
Hai Zhang, Xin-Yi Liu, Yunhua Zhao et al.· International Immunopharmaco...· 0 citations
The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses. In recent years, research on this pathway in the field of kidney diseases has expanded explosively, extending from acute kidney injury (AKI) to various pathological conditions including chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and renal cell carcinoma (RCC). This review systematically summarizes the activation mechanisms and functional diversity of the cGAS-STING pathway in different kidney diseases. In AKI, mitochondrial DNA leakage, metabolic disturbances (lipid accumulation, lactate accumulation), and post-translational modifications (e.g., LDHB K156 lactylation) collectively activate this pathway, driving sterile inflammation. In CKD and renal fibrosis, the pathway promotes metabolic reprogramming, cellular senescence, and extracellular matrix deposition through canonical (TBK1–IRF3/NF-κB) and non-canonical (STING–PERK–eIF2α) signaling axes, as well as epitranscriptional regulation (e.g., METTL3-mediated m6A modification). In DKD and LN, its overactivation mediates podocyte injury and type I interferonopathy, respectively. Of note, in RCC, this pathway primarily exerts anti-tumor immune surveillance, highlighting its highly context-dependent functions. Although preclinical studies have demonstrated the therapeutic potential of various small-molecule inhibitors (e.g., RU.521, H-151) and natural product monomers or herbal formulas, clinical translation still faces four major challenges: the dual nature of pathway function (balancing host defense versus sterile inflammation), insufficient specificity and safety of existing inhibitors, lack of predictive biomarkers for therapeutic efficacy, and drug delivery difficulties arising from renal anatomical heterogeneity. To address these bottlenecks, this review proposes next-generation precision modulation strategies, including the development of tissue/cell-specific targeted delivery systems (e.g., biomimetic nanoscavengers), application of proteolysis-targeting chimera (PROTAC) technology, intervention in upstream metabolic and mitochondrial homeostasis, modulation of post-translational modifications, and combination therapies (e.g., with SGLT2 inhibitors, immune checkpoint inhibitors, or senolytics). Finally, we discuss key future directions in this field: advancing highly selective STING inhibitors/degraders into clinical trials, establishing combinatorial biomarker panels based on urinary mtDNA/cGAMP, and achieving precision medicine stratification based on patient-specific pathway activation subtypes. In conclusion, the cGAS-STING pathway has emerged as a central hub linking kidney injury to inflammation, metabolism, and fibrosis, and its precise modulation holds transformative therapeutic promise for hundreds of millions of patients with kidney diseases worldwide.
Guang-Dong Qi, Fei Xue, Hua-Lin Sun et al.· Frontiers in Pharmacology· 0 citations
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