%0 Journal Article
%T Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin
%J -
%D 2019
%R https://doi.org/10.1038/s42255-019-0063-6
%X 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 ¦Â-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¨Chepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6¨Chepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in ¦Â-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
%U https://www.nature.com/articles/s42255-019-0063-6