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

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.