Language

English

Publication Date

6-15-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI197651

PMID

42066052

PMCID

PMC13262735

PubMedCentral® Posted Date

4-30-2026

PubMedCentral® Full Text Version

Post-print

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 patients with IPF. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-β1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin-injured (Bleo-injured) mice. EIPA exerted its antifibrotic effects by regulating amino acid uptake, mammalian target of rapamycin complex 1 (mTORC1) activation and mesenchyme homeobox1 (MEOX1) expression in activated HLFs. Fittingly, genetic inhibition of macropinocytosis also ameliorated lung fibroblast activation and pulmonary fibrosis in mice. Using IPF-derived precision cut lung slices (PCLSs), we observed robust repression of profibrotic gene expression programs in EIPA-treated PCLSs across different fibroblast subpopulations. Finally, we found that imipramine (Imi), a tricyclic antidepressant approved by the FDA, effectively inhibited macropinocytosis and ameliorated profibrotic responses in lung fibroblasts, Bleo-injured mice, and IPF-derived PCLSs. Taken together, our results suggest that macropinocytosis inhibition can be considered as a potential therapeutic strategy to treat pulmonary fibrosis.

Keywords

Animals, Humans, Fibroblasts, Mice, Pinocytosis, Lung, Idiopathic Pulmonary Fibrosis, Disease Models, Animal, Amiloride, Bleomycin, Male, Transforming Growth Factor beta1, Mechanistic Target of Rapamycin Complex 1, Cell biology, Pulmonology, Fibrosis

Published Open-Access

yes

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