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Fraxetin alleviates BLM-induced idiopathic pulmonary fibrosis by inhibiting NCOA4-mediated epithelial cell ferroptosis

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Abstract

Introduction

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung condition with few available treatments. The early driver of wound repair that contributes to IPF has been extensively identified as repetitive alveolar epithelial damage. According to recent reports, IPF is linked to ferroptosis, a unique type of cell death characterized by a fatal buildup of iron and lipid peroxidation.

Objective and method

There is little information on epithelial cells that induce pulmonary fibrosis by going through ferroptosis. In this study, we used bleomycin (BLM) to examine the impact of ferroptosis on IPF in mouse lung epithelial cells (MLE-12).

Results

We discovered that BLM increases ferroptosis in MLE-12. Additionally, we found that NCOA4 is overexpressed and plays a key role in the ferroptosis of epithelial cells throughout the IPF process. Using Molecular docking, we found that Fraxetin, a natural component extracted from Fraxinus rhynchophylla, formed a stable binding to NCOA4. In vitro investigations showed that Fraxetin administration greatly decreased ferroptosis and NCOA4 expression, which in turn lowered the release of inflammatory cytokines.

Conclusion

Fraxetin treatment significantly alleviated BLM-induced lung inflammation and fibrosis. Our findings imply that fraxetin possesses inhibitory roles in ferroptosis and can be a potential drug against IPF.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

IPF:

Idiopathic pulmonary fibrosis

ROS:

Lipid reactive oxygen species

MLE-12:

Mouse lung epithelial cells

AEC:

Alveolar epithelial cells

BALF:

Bronchoalveolar lavage

MDA:

Lipid oxidation

GSH:

Total glutathione peroxidase

ATP5a:

Oxidative phosphorylation marker

SLC7A11:

Solute carrier family members

GPX4:

Glutathione peroxidase enzyme 4

EpCAM:

Epithelial cells

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81800065, 82003769), the National Postdoctoral Science Foundation of China (2021M691292); the Postdoctoral Science Foundation of Jiangsu Province (2020Z132).

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Author notes

  1. Xiaorun Zhai, Jingyu Zhu and Jiao Li have contributed equally to this paper.

Authors and Affiliations

  1. Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China

    Xiaorun Zhai, Jiao Li, Zhixu Wang & Yunjuan Nie

  2. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, Jiangsu, China

    Jingyu Zhu

  3. Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China

    Gufang Zhang

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  1. Xiaorun Zhai
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Contributions

YN and XZ: designed the experiments; XZ, JZ, JL, and ZW: performed the experiments and analyzed the data; YN, XZ and GZ: prepared the manuscript.

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Correspondence to Yunjuan Nie.

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The animal experiments involved in this experiment were approved by the Animal Protection and Use Committee of Jiangnan University (JN. No 20211130 m1720615[501]).

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Zhai, X., Zhu, J., Li, J. et al. Fraxetin alleviates BLM-induced idiopathic pulmonary fibrosis by inhibiting NCOA4-mediated epithelial cell ferroptosis. Inflamm. Res. 72, 1999–2012 (2023). https://doi.org/10.1007/s00011-023-01800-5

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