Genetic or induced deficiencies of the transmembrane iron exporting protein ferroportin (FPN1) causes the iron misdistribution that underlies Anemia of Inflammation (AoI) and Ferroportin Disease (FD) in humans. A small molecule natural product, hinokitiol, was previously shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in DMT1- or mitoferrin-deficient zebrafish. Here we show that in FPN1-deficient flatiron mice hinokitiol redistributes iron from liver to red blood cells and thereby restores hemoglobinization. We also have further characterized the corresponding mechanism; hinokitiol first releases iron trapped within liver macrophages, then hinokitiol-Fe complexes transfer iron to transferrin (Tf), and finally the resulting Fe-Tf complexes drive red blood cell maturation in a transferrin receptor (TfR)-dependent manner. These findings provide foundational support for the use of small molecule as a molecular prosthetic to address a range of human diseases caused by iron misdistribution.

A small molecule redistributes iron from liver to erythroblasts via transferrin-dependent pathway in ferroportin-deficient mice

ACS Fall 2021

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