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

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.