Systemic iron-handling pathways

Systemic iron-handling pathways encompass the coordinated physiological processes that regulate iron absorption, transport, utilization, and storage to maintain systemic iron homeostasis [1, 9]. The central regulator of these pathways is the liver-derived peptide hormone hepcidin, which controls the systemic flux of iron by binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter found on enterocytes, macrophages, and hepatocytes [1, 4, 9]. This regulatory axis ensures a steady supply of iron for essential functions such as hemoglobin synthesis in erythropoiesis and mitochondrial respiration while preventing the accumulation of toxic free iron that can lead to oxidative tissue damage via Fenton chemistry [3, 10]. Dysregulation of these pathways is a hallmark of various diseases, including hereditary hemochromatosis, where hepcidin deficiency leads to systemic iron overload, and anemia of chronic disease, where inflammatory cytokines overstimulate hepcidin, causing iron sequestration and restricted erythropoiesis [1, 7, 10]. Therapeutic strategies targeting these pathways include hepcidin mimetics and ferroportin inhibitors to treat iron overload, as well as HIF-prolyl hydroxylase inhibitors and JAK inhibitors to suppress hepcidin and improve iron availability in anemias [4, 7]. Monitoring of these pathways typically involves biomarkers such as serum ferritin, transferrin saturation, and hepcidin levels to guide precision treatment [4, 10]. Additionally, iron chelators are employed to remove excess iron from tissues in chronic loading conditions [2, 5]. The complexity of these pathways requires careful management to avoid side effects such as increased susceptibility to infections or thrombotic events [7, 9]. Overall, these pathways represent a critical therapeutic landscape for managing disorders of iron imbalance and their associated systemic complications [1, 6].

Other names

Iron homeostasisSystemic iron metabolismHepcidin-ferroportin axisIron regulatory pathways

Therapeutic modulation of systemic iron involves several distinct mechanisms: hepcidin mimetics (e.g., rusfertide) and ferroportin inhibitors (e.g., vamifeport) reduce iron export to treat overload; iron chelators (e.g., deferasirox) bind and remove excess labile iron; HIF-prolyl hydroxylase inhibitors (e.g., roxadustat) and JAK inhibitors (e.g., momelotinib) suppress hepcidin production to increase iron availability for erythropoiesis.