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The cytosolic DNA-binding receptor cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity and therapeutic potential in SSc-ILD using human biospecimens, cultured fibroblasts, precision-cut lung slices and a well-accepted animal model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Expression and localisation of cGAS, cytokines and type 1 interferons were evaluated in SSc\u2011ILD lung tissues, bronchoalveolar lavage fluid and isolated lung fibroblasts.\n                      <jats:italic>CGAS<\/jats:italic>\n                      activation was assessed in a publicly available SSc-ILD single-cell RNA-sequencing dataset. Production of cytokines, type 1 interferons and \u03b1-smooth muscle actin elicited by transforming growth factor-\u03b21 or local substrate stiffness was measured in normal human lung fibroblasts\n                      <jats:italic>via<\/jats:italic>\n                      quantitative reverse transcription PCR, ELISA and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human precision-cut lung slices and the bleomycin pulmonary fibrosis model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SSc-ILD lung tissue and bronchoalveolar lavage fluid were enriched for cGAS, cytokines and type 1 interferons. The cGAS pathway showed constitutive activation in SSc-ILD fibroblasts and was inducible in normal human lung fibroblasts by transforming growth factor-\u03b21 or mechanical stimuli. In these settings, and in precision-cut lung slices, cGAS expression was paralleled by the production of cytokines, type 1 interferons and \u03b1-smooth muscle actin, which was mitigated by a small molecule cGAS inhibitor. These findings were recapitulated in the bleomycin mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>cGAS signalling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc\u2011ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.01564-2024","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T07:37:11Z","timestamp":1750145831000},"page":"2401564","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Cyclic GMP-AMP synthase expression is enhanced in systemic sclerosis-associated interstitial lung disease and stimulates inflammatory myofibroblast 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