Model of the contribution of ZIP8 to iron uptake and BMP6 production by LECs during iron overload. NTBI present in iron-loaded blood plasma is taken up, at least in part, by ZIP8 at the plasma membrane of LECs. Cellular iron loading from NTBI promotes the formation of ROS, leading to translocation of NRF2 transcription factor into the nucleus, thereby activating the transcription of the Bmp6 gene and genes encoding proteins with antioxidant properties, such as Nqo1 and Gclc. BMP6 secreted by LECs acts on neighboring hepatocytes to increase the production of the iron-regulatory hormone hepcidin. The uptake of plasma transferrin-bound iron via TFR1 (not shown) is dispensable for LEC production of BMP6 during iron overload. ROS, reactive oxygen species. Professional illustration by Somersault18:24.