Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models

Wagner, Darcy Elizabeth LU orcid ; Alsafadi, Hani N LU orcid ; Mitash, Nilay ; Justet, Aurelien ; Hu, Qianjiang ; Pineda, Ricardo ; Staab-Weijnitz, Claudia ; Korfei, Martina ; Gvazava, Nika LU and Wannemo, Kristin , et al. (2025) In Nature Communications 16(1).
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in... (More)

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Animals, Idiopathic Pulmonary Fibrosis/metabolism, YAP-Signaling Proteins, Protein-Lysine 6-Oxidase/metabolism, Signal Transduction/drug effects, Verteporfin/pharmacology, Transcription Factors/metabolism, Adaptor Proteins, Signal Transducing/metabolism, Mice, Alveolar Epithelial Cells/metabolism, Disease Models, Animal, Extracellular Matrix/metabolism, Male, Lung/pathology, Mice, Inbred C57BL, DNA-Binding Proteins/metabolism, Female, Cell Cycle Proteins/metabolism
in
Nature Communications
volume
16
issue
1
article number
7099
publisher
Nature Publishing Group
external identifiers
  • scopus:105012456235
  • pmid:40753090
ISSN
2041-1723
DOI
10.1038/s41467-025-61795-x
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
fea60a2b-b6bc-4988-baa9-ac093d54f227
date added to LUP
2025-08-13 23:28:39
date last changed
2025-08-15 03:18:42
@article{fea60a2b-b6bc-4988-baa9-ac093d54f227,
  abstract     = {{<p>Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.</p>}},
  author       = {{Wagner, Darcy Elizabeth and Alsafadi, Hani N and Mitash, Nilay and Justet, Aurelien and Hu, Qianjiang and Pineda, Ricardo and Staab-Weijnitz, Claudia and Korfei, Martina and Gvazava, Nika and Wannemo, Kristin and Onwuka, Ugochi and Mozurak, Molly and Estrada-Bernal, Adriana and Cala-Garcia, Juan and Mutze, Katrin and Costa, Rita and Bölükbas, Deniz and Stegmayr, John and Skronska-Wasek, Wioletta and Klee, Stephan and Ota, Chiharu and Baarsma, Hoeke A and Wang, Jingtao and Sembrat, John and Hilgendorff, Anne and Ding, Jun and Günther, Andreas and Chambers, Rachel and Rosas, Ivan and de Langhe, Stijn and Kaminski, Naftali and Lehmann, Mareike and Eickelberg, Oliver and Königshoff, Melanie}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; Animals; Idiopathic Pulmonary Fibrosis/metabolism; YAP-Signaling Proteins; Protein-Lysine 6-Oxidase/metabolism; Signal Transduction/drug effects; Verteporfin/pharmacology; Transcription Factors/metabolism; Adaptor Proteins, Signal Transducing/metabolism; Mice; Alveolar Epithelial Cells/metabolism; Disease Models, Animal; Extracellular Matrix/metabolism; Male; Lung/pathology; Mice, Inbred C57BL; DNA-Binding Proteins/metabolism; Female; Cell Cycle Proteins/metabolism}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-61795-x}},
  doi          = {{10.1038/s41467-025-61795-x}},
  volume       = {{16}},
  year         = {{2025}},
}