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10.1172/jci.insight.183247
1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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Bonneil, E.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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Soleimani, V.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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Borchers, C.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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Koulman, A.
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada
2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada
3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China
5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany
7Environmental Hygiene, Technical University Munich, Munich, Germany
8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany
9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America
10Department of Biology, York University, Toronto, Canada
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Published January 6, 2026 - More info
Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2α (HIF2α) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet–induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.