IRF-1 modulates hepatic ferroptosis and aggravates liver ischemia/reperfusion injury via DYRK1α

  • Animal Model Exp Med. 2026 Jun 16. doi: 10.1002/ame2.70194.
Jinping Zhang  1 ,  Jinming Zhang  2 ,  Siyuan Song  3 ,  Mingyang Li  4  5  6 ,  Liying Sun  4  5  6  7  8  9 ,  Zhijun Zhu  4  5  6  7  8 ,  Dongdong Lin  1
Affiliations
  • 1. General Surgery Department, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 2. Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • 3. Baylor College of Medicine, Houston, Texas, USA.
  • 4. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
  • 5. State Key Laboratory of Digestive Health, Beijing, China.
  • 6. Beijing Key Laboratory of Organ Cultivation and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 7. Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 8. Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.
  • 9. Department of Critical Liver Disease, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
PMID: 42299064 DOI: 10.1002/ame2.70194
Abstract

Background: The purpose is to define the contribution of the interferon regulatory factor-1-dual-specificity tyrosine phosphorylation-regulated kinase 1α (IRF-1-DYRK1α) axis to hepatocellular Ferroptosis during liver ischemia/reperfusion injury (LIRI).

Methods: Ferroptosis was induced in AML12 hepatocytes with erastin. After gain- or loss-of-function manipulation of IRF-1 and DYRK1α, we quantified Glutathione Peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4), Reactive Oxygen Species (ROS), malondialdehyde (MDA), and glutathione (GSH). In vivo, wild-type (WT) mice, IRF-1 knockout (Irf1-/-) mice, and WT mice treated with the DYRK1α inhibitor harmine underwent a 70% warm LIRI model. Liver and blood were collected for histology, serum transaminases, cytokine ELISA, protein analyses, and flow cytometry.

Results: IRF-1 knockdown attenuated LIRI, accompanied by suppression of hepatocellular Ferroptosis. DYRK1α inhibition reversed IRF-1-mediated decreases in GSH and GPX4 and prevented increases in MDA, ROS, and ACSL4 in AML12 cells, indicating DYRK1α participation in IRF-1-driven Ferroptosis. In mice, pharmacologic inhibition of DYRK1α with harmine reduced hepatic Ferroptosis and ameliorated LIRI.

Conclusion: IRF-1 aggravates LIRI, at least in part, by promoting hepatocellular Ferroptosis via DYRK1α. Targeting the IRF-1-DYRK1α axis may offer a therapeutic strategy to limit perioperative liver injury.

Keywords
ACSL4; DYRK1α; GPX4; ferroptosis; interferon regulatory factor‐1 (IRF‐1); liver ischemia–reperfusion injury; oxidative stress.
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