Hepcidin

Hepcidin is a peptide hormone produced primarily by the liver and is the principal regulator of systemic iron homeostasis. The human gene HAMP encodes the hepcidin precursor, which is processed to the mature peptide hepcidin-25, the active circulating form.

Mechanism of action and role in iron metabolism

Hepcidin controls iron levels by binding to ferroportin, the cellular iron exporter expressed on enterocytes, macrophages, and hepatocytes. Binding induces ferroportin internalization and lysosomal degradation, reducing iron efflux into plasma. As a result, dietary iron absorption and iron recycling from senescent red blood cells are limited, lowering serum iron and transferrin saturation while iron stores may remain elevated.

Regulation

Hepcidin expression is increased by iron overload and inflammatory signals, notably interleukin-6, which operate via the JAK-STAT pathway. It is decreased by iron deficiency, increased erythropoietic activity, and hypoxia. Disruptions in regulation can contribute to iron disorders; for example, low hepcidin can lead to iron overload, while excessive hepcidin can cause iron-restricted erythropoiesis.

Clinical relevance

Hepcidin is a key biomarker and therapeutic target in disorders of iron metabolism. Serum or plasma hepcidin measurements, in combination with ferritin and inflammatory markers, help differentiate iron deficiency from anemia of inflammation. Genetic defects affecting hepcidin production or regulation contribute to conditions such as hereditary iron-loading syndromes and iron-refractory iron deficiency anemia. Therapeutic approaches under investigation include hepcidin mimetics for iron overload and antagonists to treat anemia of inflammation.