Led by faculty in the Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the research identifies how a signaling pathway inside lung epithelial cells known as YAP-TEAD regulates the activity of lysyl oxidase, enzymes that stiffen lung tissue. Those enzymes crosslink and harden the extracellular matrix (ECM), the structural scaffold of the lung. When this process runs unchecked, it sets off a vicious cycle of tissue stiffening, scarring, and ultimately, loss of lung function.
Pulmonary fibrosis is marked by excessive ECM production and deposition, which thickens and scars the lung, making it harder to breathe. While fibroblasts have long been considered the primary culprits, this study highlights a previously overlooked role for epithelial cells, which line alveoli in the lungs.
“In this study, we identified a previously unrecognized mechanism of how epithelial cells contribute to extracellular matrix crosslinking and deposition in lung fibrosis,” said senior author Melanie Königshoff, M.D., Ph.D., professor in Department of Medicine at the University of Pittsburgh. “It represents a paradigm shift in how we think about therapeutic targets for this devastating disease.”
Königshoff and her team used cutting-edge techniques, including single-cell omics and human tissue-based translational models, to trace how YAP-TEAD signaling in epithelial cells triggers lysyl oxidase activity. The result is a feedback loop: stiffened lung tissue activates the pathway, which in turn drives more ECM crosslinking, amplifying fibrosis.
Perhaps most encouraging, the researchers demonstrated that blocking this pathway with an FDA-approved drug significantly reduced fibrotic signaling and overall fibrosis in preclinical models. The finding raises the possibility that existing therapies could be repurposed for pulmonary fibrosis, potentially speeding translation into the clinic.
Idiopathic pulmonary fibrosis (IPF), which affects approximately 3 million people worldwide, has a median survival of just three to five years. Current treatments, pirfenidone and nintedanib, slow disease progression but do not halt or reverse it. By targeting the epithelial-driven stiffening process uncovered in this study, future therapies may be able to break the cycle of fibrosis rather than just slow it.
The research team plans to further investigate how YAP-TEAD signaling could be selectively inhibited in patients, and whether lysyl oxidase activity might serve as a biomarker for disease progression. If successful, this work could usher in a new generation of therapies that interrupt fibrosis at its source, giving patients not just more time, but the possibility of better quality of life.
“This study has evolved over several years and been made possible by an international collaborative effort from scientists and clinicians worldwide,” Königshoff said. “I feel lucky to be part of such an amazing group of people unified by their aim to combat devastating lung diseases, such as pulmonary fibrosis.”
Other authors from the University of Pittsburgh on the study included Nilay Mitash, Ph.D., Qianjiang Hu, D.V.M., Ph.D., Ricardo Pineda, Ph.D., Kristin Wannemo, B.S., Ugochi Onwuka, B.S., Molly Mozurak, B.S., Adriana Estrada-Bernal, Ph.D., John Sembrat, M.S., and Oliver Eickelberg, M.D. Additional authors included Darcy Elizabeth Wagner Ph.D., Hani N. Alsafadi, Ph.D., Nika Gvazava, John Stegmayr, Ph.D., and Deniz Bölükbas, Ph.D., from Lund University (Sweden); Katrin Mutze, Ph.D., Rita Costa, Ph.D., Wioletta Skronska-Wasek, Ph.D., Stephan Klee, Chiharu Ota, M.D., Ph.D., Hoeke A. Baarsma, Ph.D., Anne Hilgendorff, M.D., Claudia Staab-Weijnitz, Ph.D., and Mareike Lehmann, Ph.D., from, Helmholtz Zentrum München (Germany); Jingtao Wang, M.S., and Jun Ding, Ph.D., from McGill University (Canada); Martina Korfei, Ph.D., and Andreas Günther, M.D., from Justus-Liebig-Universität Giessen (Germany); Rachel Chambers, Ph.D., from University College London; Ivan Rosas, M.D., from Baylor College of Medicine; Stijn de Langhe, Ph.D., from the Mayo Clinic; and Juan Cala-Garcia, M.D., Aurélien Justet, M.D., Ph.D., and Naftali Kaminski, M.D., from Yale University.
This research was supported by the National Institutes of Health (R01 HL146519), Vetenskapsrådet (2018-02352), European Research Council (EU Framework Programme for Research and Innovation H2020, 805361/EC; H2020 Priority Excellent Science; H2020 Excellent Science); and Deutsche Forschungsgemeinschaft (512453064, BfR 60-0102-01.P588).