Model of iron (Fe) uptake and BMP6 production by LSECs under iron-limited and iron-loaded conditions. When the iron supply in blood plasma in the liver sinusoid is limited, LSECs become iron deficient and therefore upregulate TFR1 levels to increase iron uptake from holo-TF. Conversely, iron loading of LSECs downregulates TFR1 levels, thus limiting iron uptake via holo-TF. When iron levels exceed TF’s iron-carrying capacity, NTBI appears in the plasma and is taken up by LSECs via a plasma membrane NTBI transporter, which remains to be identified. In iron overload, NTBI becomes the main driver of LSEC production of BMP6, which binds to BMP receptors (BMPRs) on neighboring hepatocytes, thereby activating a signaling pathway that increases the liver’s synthesis of hepcidin. Under iron-limited conditions, LSECs acquire iron via holo-TF and TFR1, which is needed for appropriate basal production of BMP6 and hepcidin. Professional illustration by Patrick Lane, ScEYEnce Studios.