Animal models and experimental medicine · 2026
IRF-1 modulates hepatic ferroptosis and aggravates liver ischemia/reperfusion injury via DYRK1α.
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Zhang Jinping, Zhang Jinming, Song Siyuan, Li Mingyang, Sun Liying, Zhu Zhijun, Lin Dongdong
Аннотация
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.
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.