A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages

Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2121400119. doi: 10.1073/pnas.2121400119. Epub 2022 Jun 22.


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.

Keywords: ferroportin disease; hemoglobinization; hinokitiol; iron misdistribution; iron redistribution.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cation Transport Proteins / deficiency
  • Ferritins / metabolism
  • Humans
  • Iron* / metabolism
  • Macrophages* / metabolism
  • Mice
  • Monoterpenes* / metabolism
  • Transferrin / metabolism
  • Tropolone / analogs & derivatives*
  • Tropolone / metabolism
  • Zebrafish / metabolism


  • Cation Transport Proteins
  • Monoterpenes
  • Transferrin
  • metal transporting protein 1
  • Tropolone
  • Ferritins
  • Iron
  • beta-thujaplicin