Faculty, Staff and Student Publications

Language

English

Publication Date

1-29-2026

Journal

Respiratory Research

DOI

10.1186/s12931-025-03479-0

PMID

41606738

PMCID

PMC12922364

PubMedCentral® Posted Date

1-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Iron is an essential nutrient for almost all organisms. However, excess iron generates reactive oxygen species and causes tissue injuries. Iron is implicated in idiopathic pulmonary fibrosis (IPF). In this study, we examined iron accumulation in fibrotic lung fibroblasts and the underlying mechanisms. We hypothesize that the downregulation of Solute Carrier Family 40 Member 1 (SLC40A1) results in iron accumulation in lung fibroblasts of IPF patients. Using a Prussian Blue iron staining, we found that iron accumulated in the fibrotic region of the lungs from IPF patients and bleomycin- and asbestos-induced lung fibrosis mice. Iron was partially co-localized with the fibroblast marker vimentin in IPF lungs. By using publicly available single cell RNA sequencing datasets, we identified SLC40A1, the only known gene involved in iron export, as a downregulated gene in alveolar fibroblasts of IPF. The downregulation of SLC40A1 was confirmed in the lung fibroblasts isolated from IPF patients and bleomycin-treated mice. The treatment of human lung fibroblasts with transforming growth factor-β1 (TGF-β1), a major cytokine elevated in IPF, reduced SLC40A1 mRNA and protein expression. TGF-β1 downregulated SLC40A1 expression via SMAD3 as determined by chromatin immunoprecipitation and luciferase promoter reporter assays. Knockdown of SLC40A1 using lentiviral shRNAs or TGF-β1 treatment induced iron accumulation in human lung fibroblasts as determined by live cell ferrous dye staining using a SiRhoNox-1 probe. Knockdown of SLC40A1 enhanced the iron-induced lung fibroblast activation. In summary, we conclude that the downregulation of SLC40A1 caused by TGF-β1 induces iron accumulation in lung fibroblasts, resulting in fibroblast activation.

Keywords

Fibroblasts, Animals, Humans, Down-Regulation, Iron, Mice, Lung, Idiopathic Pulmonary Fibrosis, Mice, Inbred C57BL, Cation Transport Proteins, Ferroportin, Cells, Cultured, Male, Female, Bleomycin

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.