Regulation of hepcidin by iron and inflammation. (A) Hepcidin regulation by iron. Binding of BMP6 to BMP receptor complex on the hepatocyte surface, in the presence of the coreceptor HJV, activates the receptor kinase to phosphorylate SMAD1, SMAD5, and SMAD8 proteins. Phosphorylated SMADs, together with SMAD4, translocate into the nucleus to induce transcription of hepcidin and of other target genes. HFE displaced from TFR1 by high circulating iron binds to TFR2 to activate hepcidin through uncertain mechanisms. TMPRSS6 cleaves HJV from the cell membrane to dampen BMP receptor signaling. Relevant sequence motifs of the hepcidin promoter are shown. (B) IL-6 and other cytokines activate the JAK2 and STAT signaling pathway to activate hepcidin via a STAT-binding motif in the hepcidin promoter. Modified and used with permission from Hentze et al.¹