Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin
Open accessAbstract
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 Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, 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 Bmp6 expression in liver sinusoid 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 homeostasis 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 control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.
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BMP6 expression is regulated by iron, possibly in the context of an antioxidant response, controlled by NRF2.
“BMP6 expression is regulated by iron,42 possibly in the context of an antioxidant response, controlled by NRF2.43”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [43]
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Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
“BMP6 expression is regulated by iron, 42 possibly in the context of an antioxidant response, controlled by NRF2.”
Thirty years of NRF2: advances and therapeutic challenges.
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- Authors
- Lim, P. J., Duarte, T. L., Arezes, J., Garcia-Santos, D., Hamdi, A., Pasricha, S.-R., Armitage, A. E., Mehta, H., Wideman, S., Santos, A. G., Santos-Gonçalves, A., Morovat, A., Hughes, J. R., Soilleux, E., Wang, C.-Y., Bayer, A. L., Klenerman, P., Willberg, C. B., Hartley, R. C., Murphy, M. P., Babitt, J. L., Ponka, P., Porto, G., & Drakesmith, H.
- Affiliations
- John Radcliffe Hospital (GB)
- Universidade do Porto (PT)
- Jewish General Hospital (CA)
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Oxford (GB)
- Oxford University Hospitals NHS Trust (GB)
- Harvard University (US)
- University of Glasgow (GB)
- University of Cambridge (GB)
- Corresponding author
- Drakesmith, Hal
- ORCID
- Lim, Pei Jin
- Duarte, Tiago L.
- Arezes, João
- Hamdi, Amel
- Pasricha, Sant-Rayn
- Armitage, Andrew E.
- Wideman, Sarah
- Morovat, Alireza
- Hughes, Jim R.
- Soilleux, Elizabeth
- Wang, Chia-Yu
- Bayer, Abraham L.
- Klenerman, Paul
- Willberg, Christian B.
- Hartley, Richard C.
- Murphy, Michael P.
- Babitt, Jodie L.
- Ponka, Prem
- Porto, Graça
- Drakesmith, Hal
- Venue
- Nature Metabolism
- Published
- 2019-05-13
- Volume
- 1
- Issue
- 5
- Pages
- 519-531
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6609153
- OpenAlex
- W2944225554
- Cited by
- 147
- References
- 10
- Citations by year
- 2026: 10 · 2025: 24 · 2024: 19 · 2023: 25 · 2022: 21 · 2021: 21 · 2020: 22 · 2019: 5
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.gla.ac.uk
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (110158/Z/15/Z, 110159/Z/ 15/Z, 109965/Z/15/Z)
- National Institute for Health and Care Research (NF-SI-0515-10005)
- Canadian Institutes of Health Research (126064_1, MOP-14100)
- Medical Research Council (MC_UU_00008/10, MC_PC_14131, MC_UU_00016/1)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK087727)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- Nrf2, iron homeostasis, hemochromatosis, beta-thalassemia, BMP6, hepcidin, erythroferrone, liver sinusoidal endothelial cells, hepatocytes, mitochondrial reactive oxygen species, iron overload, antioxidant response, Nrf2 activation
- MeSH terms
- Homeostasis, Humans, Iron, beta-Thalassemia, NF-E2-Related Factor 2, Bone Morphogenetic Protein 6, Hepcidins
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