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bioRxiv · 10.1101/2025.07.16.665213

Sustained Yap/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling

Gaona, I. P.·McCall, A. S.·Geis, N. M.·Colvard, A. C.·DiGiovanni, G. T.·Sherrill, T. P.·Singha, U. K.·Nichols, D. S.·Serezani, A. P.·David, H. E.·Cartailler, J.-P.·Shrestha, S.·Gutor, S. S.·Blackwell, T. S.·Kropski, J. A.·Gokey, J. J.
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Abstract

YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased expression of YAP/TAZ transcriptional targets compared to donor control lungs. In human lung organoids, pharmacological YAP/TAZ activation resulted in phenotype shifts of AECs into aberrant transitional states. In mice with Yap/Taz activation (YTactive) resulting from deletion of Hippo-kinases Stk3/4 in alveolar-type 2 (AT2) cells, resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including increased Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for PF.

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Gaona, I. P., McCall, A. S., Geis, N. M., Colvard, A. C., DiGiovanni, G. T., Sherrill, T. P., Singha, U. K., Nichols, D. S., Serezani, A. P., David, H. E., Cartailler, J.-P., Shrestha, S., Gutor, S. S., Blackwell, T. S., Kropski, J. A., Gokey, J. J.. 2025-07-18. Sustained Yap/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling. https://doi.org/10.1101/2025.07.16.665213

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