A model for iron sensing in LSECs. High intracellular iron levels, a consequence of the uptake of diferric transferrin via transferrin receptor 1 (Tfr1), NTBI via Zip8 or other transporter(s), or reduced iron efflux caused by hepcidin-mediated inhibition of ferroportin, promote lysosomal degradation of Rictor, a core component of mTORC2. Loss of mTORC2 activity leads to Akt inactivation, thereby enabling the nuclear translocation of Foxo1. Once in the nucleus, Foxo1 binds specific elements in the Bmp2 and Bmp6 promoters, thereby activating their transcription. Conversely, when intracellular iron levels are low because of reduced uptake and/or increased efflux, mTORC2 remains active, phosphorylating Akt. Activated Akt phosphorylates Foxo1, retaining it in the cytoplasm and thereby repressing Bmp2 and Bmp6 expression. Fpn, ferroportin; Tf, transferrin. Figure created with BioRender.com.