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There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Identify-small molecule compounds that stimulate FOXF1 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used mass spectrometry, immunoprecipitation, and the in vitro ubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1\u2013HECTD1 protein\u2013protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells in vitro. TanFe increased protein concentrations of FOXF1 and its target genes Flk1, Flt1, and Cdh5 in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs of Foxf1+\/\u2212 embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of Foxf1+\/\u2212 mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV with FOXF1 deletion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202207-1332oc","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T16:53:37Z","timestamp":1670518417000},"page":"1042-1054","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":31,"title":["Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia"],"prefix":"10.1093","volume":"207","author":[{"given":"Arun","family":"Pradhan","sequence":"first","affiliation":[{"name":"Center for Lung Regenerative Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixiao","family":"Che","sequence":"additional","affiliation":[{"name":"Center for Lung Regenerative Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Ustiyan","sequence":"additional","affiliation":[{"name":"Center for Lung Regenerative Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abid A.","family":"Reza","sequence":"additional","affiliation":[{"name":"Center for Lung Regenerative Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Pek","sequence":"additional","affiliation":[{"name":"Division of Neonatology and Pulmonary Biology"},{"name":"Center for Stem Cells and Organoid 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Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxia","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Neonatology and Pulmonary Biology"},{"name":"Center for Stem Cells and Organoid Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell N.","family":"Kotton","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Siefert","sequence":"additional","affiliation":[{"name":"Division of Bone Marrow Transplantation and Immune Deficiency, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8959-7218","authenticated-orcid":false,"given":"Assem G.","family":"Ziady","sequence":"additional","affiliation":[{"name":"Division of Bone Marrow Transplantation and Immune Deficiency, 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