Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.
Lim PJ., Duarte TL., Arezes J., Garcia-Santos D., Hamdi A., Pasricha S-R., Armitage AE., Mehta H., Wideman S., Santos AG., Santos-Gonçalves A., Morovat A., Hughes JR., Soilleux E., Wang C-Y., Bayer AL., Klenerman P., Willberg CB., Hartley RC., Murphy MP., Babitt JL., Ponka P., Porto G., Drakesmith H.
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.