Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex

Chronic fibrotic disorders like idiopathic pulmonary fibrosis (IPF) are characterized by aberrant 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. The latter is governed by a spatially restricted ITGB6/TGFβ1/SMAD3 signaling axis in fibrotic regions of IPF lungs and in murine lungs characterized by chronic epithelial remodeling. Mechanistically, SMAD3 directly regulates dysplastic transitional cell (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 DTCs 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.