Ferroportin Biology and Iron Homeostasis

Ferroportin is the sole known cellular iron exporter in vertebrates, mediating the transfer of dietary and recycled iron into the bloodstream. Expressed predominantly on the basolateral membrane of duodenal enterocytes, splenic macrophages and hepatocytes, ferroportin maintains systemic iron balance by releasing ferrous iron (Fe2+) for transport bound to transferrin. This export process is tightly regulated by hepcidin, a peptide hormone produced by hepatocytes in response to iron loading and inflammation. Hepcidin binds ferroportin, triggering its internalisation and lysosomal degradation, thus reducing plasma iron levels. Conversely, in states of iron deficiency or increased erythropoietic demand, hepcidin synthesis falls, allowing ferroportin to shuttle iron into circulation. Dysregulation of this axis underlies clinical disorders such as hereditary haemochromatosis, iron‐loading anaemias and anaemia of chronic disease. Recent advances in structural biology and transporter biochemistry have elucidated key mechanisms of ion binding, conformational cycling and hormonal inhibition. These insights inform the development of targeted therapies—ranging from hepcidin mimetics and antagonists to small molecules that stabilise ferroportin at the cell surface—offering promise for the treatment of iron‐related pathologies and for modulating iron availability in infection and cancer.

Research from Nature Portfolio

High‐resolution cryo-electron microscopy of a primate ferroportin homologue has revealed the structural basis of metal ion transport and inhibition. The structure defines two distinct ion‐binding sites within a clamshell‐like architecture and demonstrates that each Fe2+ ion is exported in exchange for two H+ ions, establishing an electroneutral antiport mechanism. Binding of hepcidin occurs between the two domains and sterically blocks one of the metal‐binding sites, clarifying how hormone engagement arrests the transport cycle and offering a blueprint for pharmacological intervention.

Studies on a bacterial ferroportin homologue complexed with calcium have uncovered an essential role for Ca2+ as a transport cofactor. Although Ca2+ itself is not translocated, its occupancy of a defined binding pocket promotes conformational rearrangements that facilitate the transition between inward‐ and outward‐facing states. This work not only illuminates the molecular choreography of iron efflux but also suggests a physiological link between plasma calcium levels and iron homeostasis.

Ferroportin Biology and Iron Homeostasis publication trend

The graph below shows the total number of articles in ferroportin biology and iron homeostasis across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroportin: The only characterized iron exporter in mammals, responsible for cellular iron efflux.

Hepcidin: A liver-derived peptide hormone that binds ferroportin to induce its internalisation and degradation.

Minihepcidin: A truncated synthetic peptide mimicking hepcidin’s active residues with enhanced ferroportin‐inhibitory activity.

Antiporter: A transporter that exchanges one ion or molecule for another across a membrane in opposite directions.

Conformational cycle: The series of structural rearrangements a transporter undergoes to translocate substrates.

References

1. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. International Journal of Molecular Sciences (2021).
2. Structural basis of ion transport and inhibition in ferroportin. Nature Communications (2020).
3. Calcium is an essential cofactor for metal efflux by the ferroportin transporter family. Nature Communications (2018).
4. Structural basis of ferroportin inhibition by minihepcidin PR73. PLOS Biology (2023).
5. Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects. Biomolecules (2023).