Iron homeostasis and uptake pathways

Iron homeostasis and uptake pathways represent the integrated biological systems responsible for maintaining optimal iron levels, which are essential for oxygen transport, DNA synthesis, and mitochondrial function [1, 13]. The central regulatory mechanism is the hepcidin-ferroportin axis, where the liver-derived hormone hepcidin binds to and induces the degradation of ferroportin, the only known cellular iron exporter [2, 11]. This interaction controls the release of iron from duodenal enterocytes, macrophages, and hepatocytes into the plasma, where it is transported by transferrin and internalized via transferrin receptors [2, 13]. Dysregulation of these pathways is a hallmark of various diseases, including iron deficiency anemia, hereditary hemochromatosis, and anemia of chronic disease, where inflammation-induced hepcidin leads to iron sequestration [5, 11]. Furthermore, iron's role in generating reactive oxygen species via the Fenton reaction links these pathways to ferroptosis and neurodegenerative diseases [3, 10]. Therapeutic interventions include hepcidin mimetics like rusfertide to treat iron overload, ferroportin inhibitors like vamifeport, and iron chelators such as deferoxamine to mitigate toxicity [4, 11]. In infectious diseases, bacterial iron acquisition systems are targeted by 'Trojan horse' antibiotics like cefiderocol, which exploit siderophore-mediated uptake to bypass resistance mechanisms [7, 8].

Other names

Iron metabolismSystemic iron regulationIron acquisition pathwaysHepcidin-ferroportin axis

Drugs targeting these pathways work by modulating iron absorption and export via the hepcidin-ferroportin axis, chelating excess iron to prevent oxidative damage, or exploiting iron uptake systems for targeted drug delivery.