Chronic TGFβ1 Signaling Drives Dysplastic Alveolar-Basal Metaplasia through a KRT17-Stratifin migratory complex

Chronic fibrotic disorders like idiopathic pulmonary fibrosis (IPF) are characterized by dysplastic alveolar regeneration and severely limited treatment options. Identification of the mechanisms driving aberrant epithelial repair can lead to new viable therapeutic targets. Using integrated single nucleus ATAC- and RNA-sequencing on human lungs and an in vitro model of dysplastic repair, we identify two distinct regenerative trajectories for alveolar type 2 (AT2) cells: a resolvable euplastic repair trajectory and a persistent non-resolving dysplastic repair trajectory, which is governed by a spatially restricted ITGB6/TGFβ1/SMAD3 signaling axis in fibrotic regions of IPF lungs and murine lungs characterized by chronic epithelial remodeling. Mechanistically, SMAD3 directly regulates DTC markers, including KRT17 and Stratifin. We show that TGFβ1 signaling promotes a physical interaction between KRT17 and Stratifin at the leading edge of migrating dysplastic transitional cells in vitro and in vivo, which is essential for their migratory capacity. These findings collectively define the molecular regulation of AT2-driven dysplastic regeneration and identify TGFβ1-induced KRT17-Stratifin axis as a central driver of pathological epithelial remodeling in chronic fibrosis, which can be targeted therapeutically to tilt the balance in favor of euplastic regeneration.