Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis

Biochim Biophys Acta Mol Basis Dis. 2021 Dec 1;1867(12):166204. doi: 10.1016/j.bbadis.2021.166204. Epub 2021 Jun 24.


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.

Keywords: Alveolar type II cells; Deferoxamine; Ferroptosis; Iron deposition; Pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Cation Transport Proteins / genetics
  • Deferoxamine / pharmacology
  • Disease Models, Animal
  • Ferroptosis / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Iron / adverse effects
  • Iron / metabolism*
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Reactive Oxygen Species / metabolism
  • Receptors, Transferrin / genetics


  • Cation Transport Proteins
  • Reactive Oxygen Species
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • metal transporting protein 1
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Bleomycin
  • Iron
  • Deferoxamine