2. Academic Validation
  3. UHRF1-mediated ferroptosis promotes pulmonary fibrosis via epigenetic repression of GPX4 and FSP1 genes

UHRF1-mediated ferroptosis promotes pulmonary fibrosis via epigenetic repression of GPX4 and FSP1 genes

  • Cell Death Dis. 2022 Dec 24;13(12):1070. doi: 10.1038/s41419-022-05515-z.
Yi Liu # 1,  Demin Cheng # 2,  Yue Wang 2,  Sichuan Xi 3,  Ting Wang 4,  Wenqing Sun 2,  Guanru Li 2,  Dongyu Ma 2,  Siyun Zhou 2,  Ziwei Li 2,  Chunhui Ni 5 6
Affiliations

Affiliations

  • 1 Gusu School, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 3 Thoracic Epigenetics Section, Thoracic Surgery Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
  • 4 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210000, China.
  • 5 Gusu School, Nanjing Medical University, Nanjing, 211166, China. chni@njmu.edu.cn.
  • 6 Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. chni@njmu.edu.cn.
  • # Contributed equally.
PMID: 36566325 DOI: 10.1038/s41419-022-05515-z
Abstract

Pulmonary fibrosis (PF), as an end-stage clinical phenotype of interstitial lung diseases (ILDs), is frequently initiated after alveolar injury, in which Ferroptosis has been identified as a critical event aggravating the pathophysiological progression of this disease. Here in, a comprehensive analysis of two mouse models of pulmonary fibrosis developed in our lab demonstrated that lung damage-induced Ferroptosis of alveolar epithelial Type2 cells (AEC2) significantly accumulates during the development of pulmonary fibrosis while Ferroptosis suppressor genes GPX4 and FSP1 are dramatically inactivated. Mechanistically, upregulation of de novo methylation regulator Uhrf1 sensitively elevates CpG site methylation levels in promoters of both GPX4 and FSP1 genes and induces the epigenetic repression of both genes, subsequently leading to Ferroptosis in chemically interfered AEC2 cells. Meanwhile, specific inhibition of UHRF1 highly arrests the Ferroptosis formation and blocks the progression of pulmonary fibrosis in both of our research models. This study first, to our knowledge, identified the involvement of Uhrf1 in mediating the Ferroptosis of chemically injured AEC2s via de novo promoter-specific methylation of both GPX4 and FSP1 genes, which consequently accelerates the process of pulmonary fibrosis. The above findings also strongly suggested Uhrf1 as a novel potential target in the treatment of pulmonary fibrosis.

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