N-phenylquinazolin-4-amine-based EGFR TKIs suppress pulmonary fibrosis by modulating the EGFR/ERBB3 axis in epithelial-macrophage interaction.
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| Title: | N-phenylquinazolin-4-amine-based EGFR TKIs suppress pulmonary fibrosis by modulating the EGFR/ERBB3 axis in epithelial-macrophage interaction. |
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| Authors: | Kim JH; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea., Choi SH; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea., Nam JK; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea., Park MS; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea., Seo HR; Advanced Biomedical Research Lab, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea., Choi I; Medicinal Chemistry, Institut Pasteur Korea, Seongnam-si, Gyeonggi do, Republic of Korea., Lee HJ; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea.; College of Veterinary Medicine, Jeju National University, Jeju, Republic of Korea., Cho J; Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea., Lee J; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea., Lee YJ; Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea. yjlee8@kirams.re.kr. |
| Source: | Communications biology [Commun Biol] 2025 Dec 01; Vol. 8 (1), pp. 1723. Date of Electronic Publication: 2025 Dec 01. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]- |
| MeSH Terms: | ErbB Receptors*/metabolism , ErbB Receptors*/antagonists & inhibitors , ErbB Receptors*/genetics , Receptor, ErbB-3*/metabolism , Receptor, ErbB-3*/genetics , Pulmonary Fibrosis*/drug therapy , Pulmonary Fibrosis*/metabolism , Protein Kinase Inhibitors*/pharmacology , Quinazolines*/pharmacology , Macrophages, Alveolar*/drug effects , Macrophages, Alveolar*/metabolism, Animals ; Mice ; Humans ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Male ; Quinazolinones/pharmacology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Bleomycin ; Disease Models, Animal |
| Abstract: | 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. (© 2025. The Author(s).) |
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| Grant Information: | NRF-2020M2D9A2093964 National Research Foundation of Korea (NRF); NRF-2023R1A2C20072227 National Research Foundation of Korea (NRF); NRF-2023M3A9G6057281 National Research Foundation of Korea (NRF); KIRAMS, 50531-2025 National Research Foundation of Korea (NRF) |
| Substance Nomenclature: | EC 2.7.10.1 (ErbB Receptors) EC 2.7.10.1 (Receptor, ErbB-3) 0 (Protein Kinase Inhibitors) 0 (Quinazolines) EC 2.7.10.1 (EGFR protein, mouse) EC 2.7.10.1 (EGFR protein, human) 0 (Quinazolinones) EC 2.7.10.1 (ErbB3 protein, mouse) EC 2.7.10.1 (ERBB3 protein, human) 11056-06-7 (Bleomycin) |
| Entry Date(s): | Date Created: 20251201 Date Completed: 20251201 Latest Revision: 20251204 |
| Update Code: | 20251204 |
| PubMed Central ID: | PMC12669636 |
| DOI: | 10.1038/s42003-025-08940-w |
| PMID: | 41326761 |
| Database: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | 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.<br /> (© 2025. The Author(s).) |
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| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-025-08940-w |