2. Academic Validation
  3. Ferroptosis triggered by STAT1- IRF1-ACSL4 pathway was involved in radiation-induced intestinal injury

Ferroptosis triggered by STAT1- IRF1-ACSL4 pathway was involved in radiation-induced intestinal injury

  • Redox Biol. 2023 Aug 18;66:102857. doi: 10.1016/j.redox.2023.102857.
Peizhong Kong 1,  Miaomiao Yang 2,  Ying Wang 3,  K N Yu 4,  Lijun Wu 5,  Wei Han 6
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, PR China.
  • 2 The First Affiliated Hospital of Anhui Medical University, Hefei, 230011, PR China; Anhui Public Health Clinical Center, Hefei, 230011, PR China.
  • 3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, PR China.
  • 4 Department of Physics, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, 999077, Hong Kong, China; State Key Laboratory in Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, 999077, Hong Kong, China.
  • 5 Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, PR China.
  • 6 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, PR China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, 215006, PR China. Electronic address: hanw@hfcas.ac.cn.
PMID: 37611494 DOI: 10.1016/j.redox.2023.102857
Abstract

Radiation-induced intestinal injury (RIII), a common gastrointestinal complication caused by radiotherapy on pelvic, abdominal and retroperitoneal tumors, seriously affects the life quality of patients and may result in termination of radiotherapy. At present, the pathogenesis of RIII has not been fully understood. Herein, we demonstrated that Ferroptosis played a critical role in RIII occurrence. The RNA sequencing analysis strongly hinted Ferroptosis was involved in RIII mice. In line with this, the levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), markers of lipid peroxidation, remarkably increased in RIII mice. And the Ferroptosis inhibitor, Ferrostatin-1 (Fer-1), improved the mice survival and alleviated intestinal fibrosis in vivo. Moreover, our results revealed that arachidonic acid (AA) enhanced Ferroptosis in cultured intestinal epithelial cells (IECs) and organoids in vitro after irradiation, and AA gavage aggravated RIII in mice. Mechanistic studies revealed the level of ACSL4 protein significantly increased in mouse jejunums and IECs after irradiation. Radiation-induced Ferroptosis in IECs was also prevented following ACSL4 knockdown or with the function inhibitor of ACSL4. Furthermore, we found that transcription of ACSL4 induced by irradiation was regulated by STAT1/IRF1 axis, and AMPK activation triggered by AA negatively regulated radiation-induced Ferroptosis. Taken together, our results suggest that Ferroptosis mediates RIII and reducing dietary AA intake as well as targeting the STAT1-IRF1-ACSL4 axis or AMPK may be the potential approaches to alleviate RIII.

Keywords

ACSL4; Arachidonic acid; Ferroptosis; Lipid peroxidation; Radiation-induced intestinal injury.

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