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<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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月2日

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  • Darcy Elizabeth Wagner,
  • Hani N. Alsafadi,
  • Nilay Mitash,
  • Aurelien Justet,
  • Qianjiang Hu,
  • Ricardo Pineda,
  • Claudia Staab-Weijnitz,
  • Martina Korfei,
  • Nika Gvazava,
  • Kristin Wannemo,
  • Ugochi Onwuka,
  • Molly Mozurak,
  • Adriana Estrada-Bernal,
  • Juan Cala-Garcia,
  • Katrin Mutze,
  • Rita Costa,
  • Deniz Bölükbas,
  • John Stegmayr,
  • Wioletta Skronska-Wasek,
  • Stephan Klee,
  • Chiharu Ota,
  • Hoeke A. Baarsma,
  • Jingtao Wang,
  • John Sembrat,
  • Anne Hilgendorff,
  • Jun Ding,
  • Andreas Günther,
  • Rachel Chambers,
  • Ivan Rosas,
  • Stijn de Langhe,
  • Naftali Kaminski,
  • Mareike Lehmann,
  • Oliver Eickelberg,
  • Melanie Königshoff

摘要

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.