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  2. Iron dysregulation and ferroptosis are associated with pulmonary fibrosis: Insight from idiopathic pulmonary fibrosis, systemic sclerosis, and COVID-19 patients

Iron dysregulation and ferroptosis are associated with pulmonary fibrosis: Insight from idiopathic pulmonary fibrosis, systemic sclerosis, and COVID-19 patients

  • J Trace Elem Med Biol. 2025 Aug 22:91:127728. doi: 10.1016/j.jtemb.2025.127728.
Shuai Jiang 1 Xiangguang Shi 2 Xiangzhen Kong 3 Yahui Chen 4 Weiqing Xu 5 Meng Hao 6 Dong Wei 7 Fei Gao 7 Fudi Wang 8 Weilin Pu 9 Jing Liu 6 Qingmei Liu 2 Yanyun Ma 10 Jingyu Chen 11 Jiucun Wang 12
Affiliations

Affiliations

  • 1 Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China.
  • 2 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Division of Rheumatology, Shanghai Integrated Traditional Chinese and Western Medicine Hospital, Shanghai, China; MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, Human Phenome Institute, school of Life Sciences, Fudan University, Shanghai, China.
  • 4 Division of Rheumatology, Shanghai Integrated Traditional Chinese and Western Medicine Hospital, Shanghai, China.
  • 5 Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, Human Phenome Institute, school of Life Sciences, Fudan University, Shanghai, China.
  • 7 Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
  • 8 Nutrition Discovery Innovation Center, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou, China.
  • 10 MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, Human Phenome Institute, school of Life Sciences, Fudan University, Shanghai, China; Institute for Six-sector Economy, Fudan University, Shanghai, China.
  • 11 Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China. Electronic address: chenjy@wuxiph.com.
  • 12 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, Human Phenome Institute, school of Life Sciences, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China. Electronic address: jcwang@fudan.edu.cn.
Abstract

Background: Pulmonary fibrosis (PF) is the leading cause of death in many lung diseases due to inflammation, tissue damage, Infection, or Other contributing factors. Iron metabolism and Ferroptosis have been reported to participate in some PF diseases, but the universality remains elusive.

Methods: Herein, comparative studies were conducted among idiopathic pulmonary fibrosis (IPF), immune-associated systemic sclerosis (SSc), and infectious COVID-19. The iron level was evaluated by Perls' staining and ferritin level. Ferroptosis was detected by immunohistochemistry (malondialdehyde, oxidizing lipids, GPX4, and FSP1) and transmission electron microscopy. The results were also validated by public datasets analysis. Furthermore, the iron homeostasis and Ferroptosis signatures were studied in the SARS-Cov-2 spike protein-induced PF cell model. The iron-mediated inflammation and fibrosis in PF were evaluated both in vitro and in vivo.

Results: We found that COVID-19 patients showed the most severe pulmonary damage and fibrosis signature. COVID-19 and SSc-PF patients have more obvious immune cell infiltration with CD11c+ monocytes and CD68 + macrophages. Iron overload and Ferroptosis were common in PF, while COVID-19 patients showed distinct iron metabolism signatures with higher expression of HO-1. Among all Ferroptosis markers, IPF patients showed the highest E06 level, COVID-19 and SSc-PF had both higher levels of MDA and 4HNE. Further studies showed iron overload and Ferroptosis occurred mainly in alveolar type II cells and macrophages. Deferoxamine (DFO) and Ferrostatin-1 (Fer1) effectively prevented malondialdehyde production and IL-6 upregulation. DFO and Fer1 alleviated fibrosis in mice.

Conclusions: Our study demonstrates that iron overload and Ferroptosis are common signatures in PF and represent potential therapeutic targets.

Keywords

Ferroptosis; Iron metabolism; Mitochondrial injury; Pulmonary fibrosis.

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