FOXF1基因突变与肺泡毛细血管发育不良及肺发育不全相关。FOXF1编码间充质叉头盒（FOX）转录因子。虽然FOXF1的前线血管生长因子功能得到了广泛研究，但在肺发育期间间充质上皮信号通路中FOXF1的作用尚未被明确。我们利用小鼠肺脏器官oid证实S52F FOXF1突变（发现于ACDMPV患者体内）可促进2型肺泡上皮细胞（AEC2）中的典型WNT/β-catenin信号通路，导致AEC2增殖增多，而AEC2进一步分化为AEC1则减少。Foxf1WT / S52F肺纤维母细胞和野生上皮细胞组成的肺泡脏器在Matrigel上生长更快，并表现出AEC2增生。Foxf1WT/S52F胚胎肺部也存在AEC2细胞增生和AEC1减少。在肺脏器官oid和Foxf1WT / S52F小鼠的AEC2中激活了典型的WNT/β-catenin信号通路，并降低了肺纤维母细胞中非典型WNT5A配体的表达。机械上，FOXF1通过位于Wnt5a基因的第一个内含子中的一个演变保守的+6320 / +6326区域，直接激活Wnt5a基因转录。站点定向突变+6320 / +6326区域可防止FOXF1激活Wnt5a增强子的转录活性。外源的WNT5A配体治疗阻止了S52F FOXF1突变对肺泡脏器典型WNT /β-catenin信号通路异常增生的影响，并恢复了AEC1分化。FOXF1或WNT5A的激活可能提供一个有吸引力的策略，以改善ACDMPV患者的肺功能。

Mutations in the FOXF1 gene, encoding the mesenchymal Forkhead Box (FOX) transcription factor, are linked to Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV), a severe congenital disorder associated with the loss of alveolar capillaries and lung hypoplasia. While proangiogenic functions of FOXF1 have been extensively studied, the role of FOXF1 in mesenchymal-epithelial signaling during lung development remains uncharacterized. Herein, we utilized murine lung organoids to demonstrate that the S52F FOXF1 mutation (found in ACDMPV patients) stimulates canonical WNT/β-catenin signaling in type 2 alveolar epithelial cells (AEC2s), leading to increased proliferation of AEC2s and decreased differentiation of AEC2s into AEC1s. Alveolar organoids containing Foxf1WT/S52F lung fibroblasts and wild-type epithelial cells grew faster on Matrigel and exhibited AEC2 hyperplasia. AEC2 hyperplasia and loss of AEC1s were found in the lungs of Foxf1WT/S52F embryos, a mouse model of ACDMPV. Activation of canonical WNT/β-catenin signaling in AEC2s of lung organoids and Foxf1WT/S52F mice was associated with decreased expression of non-canonical WNT5A ligand in lung fibroblasts. Mechanistically, FOXF1 directly activates the Wnt5a gene transcription through an evolutionarily conserved +6320/+6326 region located in the first intron of the Wnt5a gene. Site-directed mutagenesis of the +6320/+6326 region prevented the transcriptional activation of the Wnt5a enhancer by FOXF1. Treatment with exogenous WNT5A ligand inhibited the effects of the S52F FOXF1 mutation on canonical WNT/β-catenin signaling in alveolar organoids, preventing aberrant AEC2 cell expansion and restoring differentiation of AEC1s. Activation of either FOXF1 or WNT5A may provide an attractive strategy to improve lung function in ACDMPV patients.