cGAS-STING/NF-κB signaling pathway

Overview

The cGAS-STING/NF-κB signaling pathway is an innate immune signaling axis that links detection of cytosolic DNA to inflammatory gene expression. In this pathway, cyclic GMP-AMP synthase (cGAS) senses aberrant DNA in the cytoplasm and activates STING, which then promotes downstream signaling events that can converge on NF-κB activation. NF-κB is a central transcription factor controlling the expression of proinflammatory cytokines, chemokines, and other mediators of immune and stress responses.

Biologically, this pathway is important in host defense, but excessive or chronic activation can contribute to inflammatory tissue injury, tumor-promoting inflammation, and neuroinflammatory processes. Because of this dual role, the cGAS-STING/NF-κB signaling pathway is increasingly studied as a therapeutic target in cancer, inflammatory disease, and disorders involving sterile inflammation. In the recent literature provided here, it appears in the context of inflammatory and vascular remodeling in triple-negative breast cancer, where pathway inhibition was associated with suppression of the inflammatory microenvironment.

Focus of Latest Publications

Recent investigations have established the cGAS-STING/NF-κB signaling axis as a critical pathogenic driver across diverse disease contexts, including senescence-driven fibrosis, age-related bone loss, inflammatory skin disease, and cancer microenvironment dysregulation. This cytosolic DNA-sensing pathway, wherein mitochondrial DNA leakage activates the cGAS-STING complex to trigger NF-κB-dependent inflammatory transcription, has emerged as a convergent node integrating multiple cellular stressors with pathological inflammation.

In pulmonary fibrosis, the natural compound emodin suppressed radiation-induced pathology by targeting the mtDNA-cGAS-STING-NF-κB axis, preserving mitochondrial integrity and preventing mtDNA cytoplasmic leakage in senescent epithelial cells. Correspondingly, trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, was shown to impair osteoblast function and promote senescence through aberrant mtDNA-mediated cGAS-STING-NF-κB pathway activation. Experimental STING knockdown in both studies attenuated pathway-dependent senescence and tissue dysfunction, establishing the axis's necessity in disease pathology.

Therapeutic strategies have targeted STING/NF-κB signaling through distinct mechanisms. In psoriasis, the traditional medicine formula Yinxie Granules—via flavonoid components quercetin and kaempferol—directly inhibited STING to selectively suppress the STING/NF-κB axis while sparing upstream regulators, simultaneously resolving skin inflammation and vascular abnormalities. In triple-negative breast cancer, the traditional compound Babaodan suppressed cGAS-STING/NF-κB signaling to limit pro-inflammatory and pro-angiogenic signaling in the tumor microenvironment.

These findings establish the cGAS-STING/NF-κB axis as a rational therapeutic target for pathologies characterized by senescence, aberrant innate immune activation, and inflammation-driven tissue remodeling, with natural compounds and small-molecule inhibitors emerging as viable therapeutic modalities.

Key Publications

• NEWJun Biomedical publication details. (PubMed Database, 2026, PMID 42405973)
• NEWJul Donkey Milk Exosomes Protect Against Dextran Sulfate Sodium-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota. (Journal of food science, 2026, PMID 42378030): "Mechanistically, eca‐let‐7g directly targeted TLR4 3'UTR to inhibit NF‐κB, while eca‐miR‐148a targeted NLRP3 3'UTR to suppress the NLRP3‐Caspase‐1‐IL‐18 axis."
• NEWJul Robinin Attenuates Xenobiotic Enzymes, Inflammation, and Apoptosis on DMH-Induced Colon Cancer via Modulating Ras/PI3K/Akt/mTOR and NF-κB/Bax/Caspase-3 Signalling Pathways in Wistar Rats. (Journal of biochemical and molecular toxicology, 2026, PMID 42365609): "Targeting important signalling pathways, such as NF-κB and PI3K/Akt/mTOR/Ras, facilitated these results."
• NEWJun Gut Microbiota-Derived TMAO Drives MC3T3-E1 Senescence and Osteogenic Dysfunction via cGAS-STING-NF-κB Signaling: Implications for Age-Related Bone Loss. (Calcified tissue international, 2026, PMID 42366244): "NF-κB inhibition partially reversed these effects."
• NEWJun Neuroprotective mechanisms of Thai traditional brain tonic Phy-Blica-O against LPS-induced neuroinflammation: Inhibition of NF-κB in microglia and mice. (PloS one, 2026, PMID 42361074): "This study provides the first experimental evidence that PBO alleviates lipopolysaccharide (LPS)-induced neuroinflammation (a process strongly linked to the development of neurodegenerative diseases) through the NF-κB signaling pathway."
• NEWJun Genistein from Thai Fermented Soybean (Thua-nao) Attenuates Osteoarthritis Pathogenesis via Dual Inhibition of NF-κB and MAPK Signaling: Evidence from Ex Vivo, Computational, and In Vitro Models. (Journal of agricultural and food chemistry, 2026, PMID 42290531): "Computational analysis predicted genistein to inhibit NF-κB and MAPK signaling effectively, with high gastrointestinal absorption."
• NEWJun Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury. (Journal of medicinal chemistry, 2026, PMID 42284437): "...which could inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation by facilitating the interaction between ring finger protein 126 (RNF126) (an E3 ubiquitin ligase) and MyD88, thereby promoting ubiquitination and subsequent degradation of MyD88."
• NEWJul Dual targeting of cutaneous inflammation and vasculopathy via STING-NF-κB blockade underlies the anti-psoriatic efficacy of Yinxie Granules. (Chinese journal of natural medicines, 2026, PMID 42285688): "Both the STING/IRF3 and STING/NF-κB pathways were activated in moderate psoriasis, while only the STING/NF-κB pathway was hyperactivated in severe disease."
• NEWJun Huanglian Wendan Decoction attenuates hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis. (Journal of ethnopharmacology, 2026, PMID 42276391): "Huanglian Wendan Decoction attenuates hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis."
• NEWJun Discovery of 10-Shogaol from Zingiber officinale with Broad Antiviral and Anti-inflammatory Activity against Dengue and Zika Viruses Using Activity-Guided Molecular Networking. (Journal of agricultural and food chemistry, 2026, PMID 42270434): "Activation of Nrf2 by 10-shogaol induced antioxidant gene expression and inhibited inflammatory NF-κB signaling."