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The study aimed to identify small-molecule compounds that stimulate FOXF1 signaling for the treatment of Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a rare neonatal pulmonary vascular disease with no effective treatments other than lung transplant. The researchers identified TanFe, a small-molecule compound from the nitrile group, which stabilized the FOXF1 protein in the cell and disrupted FOXF1–HECTD1 protein–protein interactions, decreasing ubiquitination of the FOXF1 protein in pulmonary endothelial cells in vitro. TanFe increased protein concentrations of FOXF1 and its target genes 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. TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.
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