STING–STAT3–SOX18 Axis Drives EndMT and Epigenetic Reprogramming in SAVI Lung Fibrosis

ABSTRACT 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 TGFβ-independent STING-mediated EndMT and endothelial dysfunction, and suggesting STING as a therapeutic target for inflammatory pulmonary fibrosis.