Year: 2026
Type: preprint
Abstract: 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.
Authors: Dan Yang, Guibin Chen, Sachin Gaurav, Adriana A. de Jesus, Atul K. Mehta, Colton McNinch, Adam X. Miranda, Jinzhi Wei, Noemi Kedei, Maria Olga Hernandez, Jizhong Zou, Kaari Linask, Chyi-Chia Lee, Gauthaman Sukumar, Ying Zhang, Sara Alehashemi, Les Folio, Quan Yu, Bin Lin, Bianca Lang, Bjoern Buehring, Gregor Dueckers, Adam Reinhardt, Gregory Schulte, Deborah R. Liptzin, Seza Ozen, Arturo Borzutzky, Madeline Wong, Desiree Tillo, Natalia I. Dmitrieva, Haresh Mani, Steven D. Nathan, Jason C. Kovacic, Clifton Dalgard, Manfred Boehm, Raphaela Goldbach-Mansky
Institutions: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Cancer Institute, Center for Cancer Research, Uniformed Services University of the Health Sciences, James A. Haley Veterans' Hospital, Dalhousie University, Helios Klinikum Krefeld, Boys Town National Research Hospital, University of Washington, Hacettepe University, Pontificia Universidad Católica de Chile, Inova Fairfax Hospital, Victor Chang Cardiac Research Institute, UNSW Sydney, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7140174907
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