Yang, D.; Chen, G.; Gaurav, S.; de Jesus, A. A.; Mehta, A. K.; McNinch, C.; Miranda, A. X.; Wei, J.; Kedei, N.; Hernandez, M. O.; Zou, J.; Linask, K.; Lee, C.-C.; Sukumar, G.; Zhang, Y.; Alehashemi, S.; Folio, L.; Yu, Q.; Lin, B.; Lang, B.; Buehring, B.; Dueckers, G.; Reinhardt, A.; Schulte, G.; Liptzin, D. R.; Ozen, S.; Borzutzky, A.; Wong, M.; Tillo, D.; Dmitrieva, N. I.; Mani, H.; Nathan, S. D.; Kovacic, J. C.; Dalgard, C.; Boehm, M.; Goldbach-Mansky, R.

A high prevalence of early-onset interstitial lung disease, including pulmonary fibrosis, in pediatric patients with Stimulator of interferon genes (STING)-Associated Vasculopathy with onset in infancy (SAVI) suggests a critical role for the cGAS-STING pathway in the pathogenesis of pulmonary fibrosis. We identified an endothelial-to-mesenchymal transition (EndMT) signature in lesional lung biopsies from SAVI patients, marked by a loss of endothelial and acquisition of mesenchymal markers. Consistently, induced pluripotent stem cell-derived endothelial cells (iECs) from SAVI patients harboring gain-of-function STING1 mutations spontaneously undergo EndMT, a process rescued in isogenic-correction. In endothelial cells, STING activation induces IRF3-independent STAT3 phosphorylation, initiating a SLUG-dependent mesenchymal transcriptional program while repressing SOX18 and an epigenetically-regulated endothelial maintenance network. Our studies define a non-canonical cGAS-STING-STAT3 signaling axis that couples a mesenchymal transcriptional program with epigenetic silencing of an endothelial maintenance program, promoting TGF{beta}-independent STING-mediated EndMT and endothelial dysfunction, and suggesting STING as a therapeutic target for inflammatory pulmonary fibrosis.