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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/JCI197651

Macropinocytosis inhibition attenuates pro-fibrotic responses in lung fibroblasts and pulmonary fibrosis models

Ivan O. Rosas,1 Aaron K. McDowell-Sanchez,1 Santiago Sanchez,1 Juan D. Cala-Garcia,1 Alan R. Waich Cohen,1 Elisa Ruiz-Echartea,2 Scott A. Ochsner,2 Daniel C. Kraushaar,3 Lindsay J. Celada,1 Dandan Sun,4 Francesca Polverino,1 Cristian Coarfa,5 Neil J. McKenna,2 and Konstantin Tsoyi1

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by Rosas, I. in: PubMed | Google Scholar |

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

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1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by Sun, D. in: PubMed | Google Scholar

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by Polverino, F. in: PubMed | Google Scholar |

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by Coarfa, C. in: PubMed | Google Scholar |

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by McKenna, N. in: PubMed | Google Scholar

1Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, United States of America

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States of America

3Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, United States of America

4Department of Neurology, University of Pittsburgh, Pittsburgh, United States of America

5Department of Molecular and Cellular Biology, Baylor college of Mecicine, Houston, United States of America

Find articles by Tsoyi, K. in: PubMed | Google Scholar

Published May 1, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197651.
Copyright © 2026, Rosas et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 1, 2026 - Version history
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from IPF patients. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin (Bleo)-injured mice. EIPA exerted its antifibrotic effects by regulating amino acid (AA) uptake, mammalian target of rapamycin complex 1 (mTORC1) activation and mesenchyme homeobox1 (MEOX1) expression in activated HLFs. Fittngly, genetic inhibition of macropinocytosis also ameliorated lung fibroblast activation and pulmonary fibrosis in mice. Using IPF-derived precision cut lung slices (PCLS), we observed robust repression of profibrotic gene expression programs in EIPA-treated PCLS across different fibroblast subpopulations. Finally, we found that imipramine (Imi), a tricyclic antidepressant approved by the Food and Drug Administration (FDA), effectively inhibited macropinocytosis and ameliorated profibrotic responses in lung fibroblasts, Bleo-injured mice and IPF-derived PCLS. Taken together, our results suggest macropinocytosis inhibition can be considered as a potential therapeutic strategy to treat pulmonary fibrosis.

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  • Version 1 (May 1, 2026): In-Press Preview
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