Current model of iron sensing in the liver to regulate hepcidin production. Both tissue iron and plasma iron levels are sensed by the liver to regulate hepcidin production. Iron loading increases transferrin-bound iron (2Fe-TF) and non–transferrin-bound iron (NTBI) in the circulation (right). Iron is taken up by liver endothelial cells (ECs), which play an important role in sensing tissue iron levels. Iron loading in ECs increase BMP6 and, to a lesser extent, BMP2 expression. BMP6 is partially regulated by nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is activated by iron-induced reactive oxygen species. The increased BMP2 and BMP6 bind to HJV on the hepatocyte membrane and facilitate the formation of a signaling complex consisting of BMP type I and type II receptors (BMPR1 and BMPRII). Neogenin (Neo), a scaffold protein binding to HJV, assists with the signaling complex formation and localization. The signaling complex phosphorylates SMAD1/5/8, which binds to SMAD4 and translocates to the nucleus to induce hepcidin (Hamp) transcription. Plasma iron loading is also sensed directly by hepatocytes, where 2Fe-TF binds to TFR1 and TFR2 on the hepatocyte membrane, favoring the displacement of HFE from TFR1 and the interaction between HFE and TFR2. Both HFE and TFR2 stimulate hepcidin expression via a functional interaction with the SMAD pathway, possibly by forming a complex with HJV and stabilizing BMP type I receptor ALK3. Under low-iron conditions, BMP2 and BMP6 ligand production is reduced in ECs (left). HFE binds to TFR1, whose expression levels increase, whereas TFR2 levels decrease. Iron deficiency also increases TMPRSS6/matriptase-2 (MT2) and furin, which cleave membrane HJV to generate soluble HJV (sHJV). Suppression of BMP expression, HJV cleavage from the membrane, sequestration of HFE with TFR1, and reduced TFR2 expression all diminish BMP-SMAD signaling, thus suppressing hepcidin expression.