ArticleThe Journal of clinical investigation2025
cGAS activation converges with intracellular acidification to promote STING aggregation and pyroptosis in tumor models.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Ion-GPS nanocapsules activate calcium-permeable gates in inflammatory microglia for nerve function recovery.Bioactive materials · 2026Article
- The cGAS-STING/MITA pathway in innate antiviral immunity and beyond.Cell insight · 2026Review
- The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential.The Journal of clinical investigation · 2026Review
- Cold exposure-induced loss of beneficial gut bacterial sEV is associated with the pathogenesis of bone loss through pyroptosis pathway.Journal of nanobiotechnology · 2026Article
- Endoplasmic Reticulum-Targeting NIR Cyanine ER800 Nanoparticles Promote Pyroptosis in Triple-Negative Breast Cancer.ACS applied materials & interfaces · 2026Article
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- Leveraging the crosstalk between cGAS-STING and pyroptosis by nanomedicine to enhance antitumor immunity.Journal of nanobiotechnology · 2026Review
- Phase separation and the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- Targeting pyroptosis in periodontitis: mechanisms and therapeutic strategies.Frontiers in immunology · 2026Review
- Pyroptosis-induced tissue damage in kidney disease.Renal failure · 2025Review
- Inflammasomes and pyroptosis in cancer: mechanisms and therapeutic advances.Journal of hematology & oncology · 2025Review
- Targeting pyroptosis in inflammatory bowel disease: A potentially effective therapeutic approach.World journal of gastroenterology · 2025Review
- The role of cGAS-STING signaling in HPV infection and HPV-related cancers.Frontiers in immunology · 2025Review
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) pathway is intimately associated with antitumoral immunity; however, the direct involvement of this pathway in tumor cell demise remains elusive. Here, we identified a compound, dodecyl 6-hydroxy-2-naphthoate (DHN), that induces pyroptosis in melanoma cells by activating noncanonical cGAS/STING signaling. DHN targets mitochondrial protein cyclophilin D (CypD) to induce the release of mitochondrial DNA, leading to cGAS activation and cyclic GMP-AMP (cGAMP) generation. Meanwhile, DHN-caused intracellular acidification induces protein kinase R-like endoplasmic reticulum kinase (PERK) activation, which promotes STING phosphorylation and polymerization in the presence of cGAMP, thereby facilitating the aggregation of STING in the ER, which serves as a platform to recruit Fas-associated via death domain (FADD) and caspase-8, leading to caspase-8 activation and subsequent gasdermin E cleavage, which ultimately results in pyroptosis of tumor cells and tumor regression in mouse models. The occurrence of this noncanonical cGAS/STING pathway-associated pyroptosis is also observed when both cGAS is activated and intracellular pH declines. Collectively, our findings reveal a pathway that links noncanonical cGAS/STING signaling to gasdermin E-mediated pyroptosis, thereby offering valuable insights for tumor therapy.
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