期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：26
DOI：10.1073/pnas.2121400119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Iron misdistribution underlies various diseases, ranging from anemia to neurodegeneration, but approaches to addressing this general problem are lacking. We recently reported that a small molecule natural product, hinokitiol, is capable of restoring hemoglobinization in various animal models with missing iron transporters. We now show that hinokitiol is capable of redistributing iron systemically, which in turn restores iron homeostasis in ferroportin-deficient mice and in primary macrophages derived from patients with ferroportin disease. We also elucidated the stepwise mechanism of hinokitiol-mediated iron redistribution and physiological restoration. Together, these results provide foundational support for using a molecular prosthetics approach for better understanding and possibly treating iron misdistribution.
Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor–dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.
