MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Nat Metab. 2019 May;1(5):519-531. doi: 10.1038/s42255-019-0063-6. Epub 2019 May 13.
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.
铁对生命至关重要，但过量则具有毒性，因为铁催化了促氧化剂的形成，而这些促氧化剂会在一系列疾病中导致组织损伤。Nrf2 转录因子协调细胞内固有抗氧化保护反应，而肽激素铁调素维持全身铁平衡，但在血色病和β-地中海贫血中病理生理性降低。在这里，我们表明 Nrf2 被铁诱导的线粒体来源的促氧化剂激活，并在肝窦内皮细胞中驱动 Bmp6 的表达，进而增加相邻肝细胞中铁调素的合成。在 Nrf2 敲除小鼠中，口服和静脉铁对 Bmp6-铁调素反应受损，铁积累和肝损伤增加。Nrf2 的药理学激活刺激 Bmp6-铁调素轴，改善血色病中的铁平衡，并抵消β-地中海贫血中铁调素的抑制作用。我们提出，Nrf2 将细胞对过量毒性铁的感应与全身铁平衡和抗氧化反应的控制联系起来，可能是与铁相关疾病的治疗靶点。
