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<p>Although EGFR signaling plays a key role in pulmonary fibrosis (PF), its therapeutic targeting remains limited. This study evaluates N-phenylquinazolin-4-amine-based EGFR tyrosine kinase inhibitors (TKIs) in murine models of bleomycin- and radiation-induced PF. These TKIs attenuated fibrosis by modulating the alveolar epithelial EGFR/ERBB3 axis. EGFR ligands (EGF, EREG, NRG1) were upregulated in pro-inflammatory monocyte-derived alveolar macrophages during early inflammation, with sustained EGFR/ERBB3 phosphorylation in epithelial cells. EGFR/ERBB3 knockdown in human alveolar epithelial cells reduced inflammatory cytokines. Dacomitinib more effectively suppressed TNF-α, IFN-γ, and IL-6 than nintedanib, suggesting a feedback loop driving fibrosis. Elevated phosphorylated EGFR/ERBB3 in RIPF and IPF tissues, and EGFR-related gene expression in epithelial cells from IPF single-cell RNA-seq data, further support clinical relevance. These findings highlight the importance of targeting immune–epithelial EGFR/ERBB3 signaling and support EGFR TKIs as a promising antifibrotic strategy.</p>

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N-phenylquinazolin-4-amine-based EGFR TKIs suppress pulmonary fibrosis by modulating the EGFR/ERBB3 axis in epithelial–macrophage interaction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Ji-Hee Kim,
  • Seo-Hyun Choi,
  • Jae-Kyung Nam,
  • Min-sik Park,
  • Haeng Ran Seo,
  • Inhee Choi,
  • Hae-June Lee,
  • Jaeho Cho,
  • Jeeyong Lee,
  • Yoon-Jin Lee

摘要

Although EGFR signaling plays a key role in pulmonary fibrosis (PF), its therapeutic targeting remains limited. This study evaluates N-phenylquinazolin-4-amine-based EGFR tyrosine kinase inhibitors (TKIs) in murine models of bleomycin- and radiation-induced PF. These TKIs attenuated fibrosis by modulating the alveolar epithelial EGFR/ERBB3 axis. EGFR ligands (EGF, EREG, NRG1) were upregulated in pro-inflammatory monocyte-derived alveolar macrophages during early inflammation, with sustained EGFR/ERBB3 phosphorylation in epithelial cells. EGFR/ERBB3 knockdown in human alveolar epithelial cells reduced inflammatory cytokines. Dacomitinib more effectively suppressed TNF-α, IFN-γ, and IL-6 than nintedanib, suggesting a feedback loop driving fibrosis. Elevated phosphorylated EGFR/ERBB3 in RIPF and IPF tissues, and EGFR-related gene expression in epithelial cells from IPF single-cell RNA-seq data, further support clinical relevance. These findings highlight the importance of targeting immune–epithelial EGFR/ERBB3 signaling and support EGFR TKIs as a promising antifibrotic strategy.