Journal
NATURE METABOLISM
Volume 1, Issue 5, Pages 519-531Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-019-0063-6
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Funding
- UK Medical Research Council (MRC Human Immunology Unit) [MC_UU_12010/10]
- Radcliffe Department of Medicine
- FEDER funds through COMPETE
- Fundacao para a Ciencia e Tecnologia [PTDC/BIM-MET/0739/2012, SFRH/BPD/108207/2015]
- Norte 2020 Portugal Regional Operational Programme [Norte-01-0145-FEDER-000012]
- National Institutes of Health [RO1-DK087727]
- Massachusetts General Hospital
- Medical Research Council UK [MC_U105663142]
- Wellcome Trust [110159/Z/15/Z]
- Canadian Institutes of Health Research [MOP-14100, MOP-126064]
- Fundação para a Ciência e a Tecnologia [PTDC/BIM-MET/0739/2012, SFRH/BPD/108207/2015] Funding Source: FCT
- MRC [MC_UU_12010/10, MC_PC_14131, MC_UU_00008/10, MC_UU_00016/14, MC_UU_12009/15] Funding Source: UKRI
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Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.
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