Iron-handling pathway

The iron-handling pathway is a systemic and cellular network of proteins dedicated to the regulation, transport, and storage of iron, an essential but potentially toxic micronutrient (PMC5388559). At the systemic level, the pathway is governed by the hormone hepcidin, which regulates the iron exporter ferroportin to control iron absorption from the diet and release from macrophages (MDPI 2023, 15, 11631). Within cells, iron is imported via the transferrin receptor, utilized in the mitochondria for heme and iron-sulfur cluster synthesis, or stored safely within ferritin complexes. Proper functioning of this pathway is critical for erythropoiesis, DNA synthesis, and cellular respiration. Dysregulation of iron handling leads to significant pathologies, including iron-deficiency anemia and iron-overload disorders like hereditary hemochromatosis (PMC8183454). Furthermore, iron accumulation is a hallmark of several neurodegenerative diseases, such as Parkinson's and Alzheimer's, where it contributes to oxidative stress and neuronal death via ferroptosis (PMC3874558). In the context of neonatal intraventricular hemorrhage, the pathway's inability to clear blood-derived iron can lead to post-hemorrhagic hydrocephalus (Annals of Neurology 2021, 90:2). Pharmacological intervention involves the use of chelators to remove excess iron, hepcidin-targeted therapies to modulate systemic levels, and iron supplements to treat deficiency.

Other names

Iron metabolism pathwayIron homeostasis pathwaySystemic iron regulationIron regulatory pathway

Therapeutic agents targeting the iron-handling pathway function through several distinct mechanisms: iron chelators (e.g., deferoxamine) bind and sequester excess iron to prevent oxidative damage; hepcidin mimetics (e.g., rusfertide) and ferroportin inhibitors (e.g., vamifeport) reduce iron export into the circulation to treat iron overload; and iron supplements provide elemental iron to replenish stores in deficiency states (PMC5388559, PMC8183454).