Potential mechanisms by which FOXO1 regulates iron metabolism via its interaction with the BMP/SMAD pathway. Cytosolic FOXO1 is required for optimal SMAD phosphorylation. Does it facilitate BMP receptor activation or facilitate SMAD phosphorylation (denoted by P [phosphate]) by activated BMP receptors? When serum iron levels are high (eg, when animals are fed a high fat diet), HFE binds to the BMP receptor complex. This interaction requires the presence of transferrin receptor bound to iron-bound transferrin (Tf). FOXO1 interacts with pSMAD, and the 2 proteins bind in proximity to one another on the hepcidin promoter. This complex activates hepcidin (Hamp1) transcription; given the importance of FOXO1 and SMAD in other cellular programs, they may coregulate other transcriptional targets regulating metabolism, playing a systemic role in integration of iron metabolism with other metabolic pathways. This figure was created with Biorender.com.