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

• Published in: Inflammation research Vol. 72; no. 10-11; pp. 1999 - 2012
• Main Authors: Zhai, Xiaorun, Zhu, Jingyu, Li, Jiao, Wang, Zhixu, Zhang, Gufang, Nie, Yunjuan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2023; Springer Nature B.V
• Subjects: Allergology; Alveoli; Biomedical and Life Sciences; Biomedicine; Bleomycin; Cell death; Dermatology; Epithelial cells; Epithelium; Ferroptosis; Fibrosis; Immunology; Inflammation; Lipid peroxidation; Lipids; Lung diseases; Lungs; Molecular docking; Neurology; Original Research Paper; Peroxidation; Pharmacology/Toxicology; Pulmonary fibrosis; Rheumatology; Wound healing; Ferroptosis; Idiopathic pulmonary fibrosis; Fraxetin; NCOA4
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-023-01800-5

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.