Hepcidin-Ferroportin axis (Hepcidin-FPN axis)

The Hepcidin-Ferroportin axis is the primary regulatory pathway governing systemic iron homeostasis in vertebrates [12]. Hepcidin, a 25-amino acid peptide hormone synthesized by the liver, acts as the master regulator by binding to ferroportin (SLC40A1), the sole known cellular iron exporter [4, 9]. This interaction induces the internalization and degradation of ferroportin, thereby sequestering iron within macrophages and enterocytes and lowering plasma iron levels [1, 2]. Dysregulation of this axis is central to the pathogenesis of various iron-related disorders: hepcidin excess causes iron-restricted anemias such as anemia of chronic disease and iron-refractory iron-deficiency anemia (IRIDA), while hepcidin deficiency leads to iron overload conditions like hereditary hemochromatosis and beta-thalassemia [6, 12]. Therapeutic strategies targeting this axis include hepcidin mimetics (e.g., rusfertide) to treat iron overload and polycythemia vera, as well as hepcidin antagonists or ferroportin stabilizers (e.g., vamifeport) to mobilize sequestered iron for erythropoiesis in chronic anemias [1, 2, 4].

Other names

HAMP-SLC40A1 axisHAMP-FPN axisSystemic iron regulatory axisHepcidin-Ferroportin system

Hepcidin binds to the iron exporter ferroportin, inducing its internalization and lysosomal degradation, which prevents the release of iron from enterocytes and macrophages into the plasma [2, 4, 9].