cGAS-STING/NF-κB signaling pathway
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.