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
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
BACKGROUND AND PURPOSE
The molecular mechanisms underlying denervation-induced muscle atrophy remain incompletely understood, and effective therapeutic interventions are currently lacking. Tectorigenin (TG), a natural isoflavonoid, has demonstrated antioxidant and metabolic regulatory activities. This study investigated whether TG also alleviates denervation-induced muscle atrophy via activation of the AMPK/SIRT1/PGC-1α signalling pathway.
EXPERIMENTAL APPROACH
A sciatic nerve transection model was established in ICR mice to evaluate the therapeutic effects of TG. Histomorphology, oxidative stress markers, mitochondrial function and pathway activity were assessed. A nutrient deprivation-induced C2C12 myotube atrophy model was used for in vitro validation. Pathway-specific inhibitors (Compound C, EX-527 and SR18292) were applied both in vivo and in vitro to confirm mechanistic involvement.
KEY RESULTS
TG treatment significantly improved muscle wet weight ratio, myofibre cross-sectional area and myosin heavy chain expression in denervated mice. It reduced levels of atrophy-related ubiquitin ligases, attenuated oxidative stress and improved mitochondrial integrity. TG reversed the denervation-induced suppression of AMPK/SIRT1/PGC-1α signalling and downstream effectors. In C2C12 myotubes, TG dose-dependently ameliorated atrophy and up-regulated SIRT1/PGC-1α. Pharmacological inhibition of AMPK, SIRT1 or PGC-1α abolished TG's protective effects, both in vitro and in vivo.
CONCLUSIONS AND IMPLICATIONS
TG mitigates denervation-induced muscle atrophy through a multi-mechanistic approach involving activation of the AMPK/SIRT1/PGC-1α axis, enhancement of mitochondrial dynamics and restoration of redox homeostasis. This study identifies TG as a promising candidate for clinical translation in the treatment of neurogenic muscle atrophy.
Boya Liu, Fei Xue, Xingxing Fang et al.· British Journal of Pharmacol...· 0 citations
Hypertension remains a major global risk factor for cardiovascular diseases, yet current treatments face challenges such as suboptimal blood pressure control and inadequate organ protection. Plant-derived bioactive ingredients (PDBIs), with their multi-target and multi-pathway properties, offer novel strategies for hypertension management. This review systematically examines the mechanisms of major PDBIs (flavonoids, terpenoids, alkaloids) in hypertension, focusing on their regulation of vascular function, renin-angiotensin-aldosterone system and sympathetic nervous system, water-salt homeostasis, and target organ protection. Key signaling pathways involved (NF-κB, TGF-β, MAPK, PI3K/Akt) are analyzed. Clinical translation challenges, including low bioavailability and response heterogeneity, are discussed. Future research should integrate systems pharmacology, smart delivery systems, and precision medicine to advance PDBIs from traditional use to evidence-based therapy, providing a theoretical basis for developing novel antihypertensive and organ-protective strategies.
Qiqi Deng, Yonglin Zhang, Jing Pan et al.· Phytotherapy Research· 0 citations
The composition and function of the m6A modification system is summarized, with a focus on its critical roles in skeletal muscle physiology, including satellite cell fate determination, myofiber differentiation and fusion, and energy homeostasis, and the molecular mechanisms by which m6A network dysregulation contributes to skeletal muscle diseases.
Jie Wang, Haiyan Jiang, Jiacheng Sun et al.· Naunyn-Schmiedeberg's Archiv...· 1 citation
This review systematically elucidates the molecular activation mechanisms of the cGAS–STING pathway and its complex regulatory networks within tumors, with a particular focus on analyzing its dual functions—tumor immune surveillance versus tumor promotion—and the determining factors involved.
Haiyan Jiang, Zhanzhan Li, Xia Li et al.· Frontiers in Pharmacology· 2 citations
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
This review systematically elaborates on the key pathological roles and molecular mechanisms of ERS and the triggered UPR in Parkinson's disease and discusses various intervention approaches, their research progress, and associated challenges.
Xin Chen, Zihao Zhao, Xinlei Yao et al.· Biochemical Pharmacology· 6 citations
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