Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis. Cheng Haipeng,Feng Dandan,Li Xiaohong,Gao Lihua,Tang Siyuan,Liu Wei,Wu Xiaoying,Yue Shaojie,Li Chen,Luo Ziqiang Biochimica et biophysica acta. Molecular basis of disease Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in numerous human diseases. However, its role in pulmonary fibrosis, a fatal lung disease with unknown etiology, is largely unknown. Here, we investigated the role of ferroptosis in pulmonary fibrosis. We found a large amount of iron deposition in the lung tissue of patients with pulmonary fibrosis. We observed ferroptosis in alveolar type II (ATII) cells, fibrotic lung tissues of BLM-induced pulmonary fibrosis mice. BLM-induced increase in iron level was accompanied by pathological changes, collagen deposition, and ferroptosis in ATII cells, indicating iron deposition-induced ferroptosis, which promoted the development of pulmonary fibrosis. Moreover, deferoxamine (DFO) completely prevented the pro-fibrosis effects of BLM by reducing iron deposition and ferroptosis in ATII cells. Genes associated with intracellular iron metabolism and homeostasis, such as transferrin receptor 1, divalent metal transporter 1, and ferroportin-1, and showed abnormal expression levels in animal tissues and lung epithelial MLE-12 cells, which responded to BLM stimulation. Overall, we demonstrated that BLM-induced iron deposition in MLE-12 cells is prone to both mitochondrial dysfunction and ferroptosis and that DFO reverses this phenotype. In the future, understanding the role of ferroptosis may shed new light on the etiology of pulmonary fibrosis. Ferroptosis inhibitors or genetic engineering of ferroptosis-related genes might offer potential targets to treat pulmonary fibrosis. 10.1016/j.bbadis.2021.166204

Role of Ferroptosis in Lung Diseases. Xu Wenting,Deng Huimin,Hu Song,Zhang Yiguo,Zheng Li,Liu Meiyun,Chen Yuanli,Wei Juan,Yang Hao,Lv Xin Journal of inflammation research Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress and cell death. The metabolism of iron, lipids, and amino acids and multiple signalling pathways precisely regulate the process of ferroptosis. Emerging evidence has demonstrated that ferroptosis participates in the occurrence and progression of various pathological conditions and diseases, such as infections, neurodegeneration, tissue ischaemia-reperfusion injury and immune diseases. Recent studies have also indicated that ferroptosis plays a critical role in the pathogenesis of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infection and asthma. Herein, we summarize the latest knowledge on the regulatory mechanism of ferroptosis and its association with iron, lipid and amino acid metabolism as well as several signalling pathways. Furthermore, we review the contribution of ferroptosis to the pathogenesis of lung diseases and discuss ferroptosis as a novel therapeutic target for various lung diseases. 10.2147/JIR.S307081

Lipid Peroxidation and GPX4 Inhibition Are Common Causes for Myofibroblast Differentiation and Ferroptosis. Gong Yue,Wang Nan,Liu Naiguo,Dong Hongliang DNA and cell biology Ferroptosis is a new form of regulated cell death. Fibroblast-to-myofibroblast differentiation is known to be involved in the pathogenesis of idiopathic pulmonary fibrosis. Utilizing HFL1 cell line treated with transforming growth factor-β1 (TGF-β1), we investigated the relationship between ferroptosis and pulmonary fibrosis, and the function of glutathione peroxidase 4 (GPX4) in them. The results indicated that α-smooth muscle actin and collagen I () mRNA expression levels increased significantly from 24 h after TGF-β1-treatment, and further rose after TGF-β1+erastin treatment. The levels of reactive oxygen species (ROS), malondialdehyde were increased, and the levels of GPX4 mRNA and protein were reduced after treatment with TGF-β1, and all these were magnified after TGF-β1+erastin treatment. All these changes induced by TGF-β1 and erastin can be recovered by Fer-1 treatment. The cell viability rate was decreased significantly when treated with TGF-β1+erastin, but no obvious variation of cell viability was found in TGF-β1-treated group and in other groups, suggesting that ROS, lipid peroxidation, and GPX4 inhibition are not sufficient conditions for ferroptosis. Collectively, our study reveals that ROS, lipid peroxidation, and GPX4 play important roles in pulmonary fibrosis and ferroptosis induced by erastin. Erastin promoted fibroblast-to-myofibroblast differentiation by increasing lipid peroxidation and inhibiting the expression of GPX4. Fer-1 may inhibit pulmonary fibrosis and ferroptosis through suppressing lipid peroxidation and enhancing GPX4 expression. 10.1089/dna.2018.4541