Hepcidin is a peptide hormone that functions as the master regulator of systemic iron metabolism. Its primary role is control of iron absorption, iron recycling, plasma iron concentration, and tissue iron distribution. Hepcidin regulates how much iron enters the bloodstream from intestinal enterocytes, macrophages involved in red blood cell recycling, and hepatic storage cells. Through these actions, the hormone maintains iron availability for oxygen transport, mitochondrial energy production, DNA synthesis, and numerous iron-dependent enzymes while preventing excess free iron accumulation.
The key biological action of hepcidin is binding to ferroportin, the major cellular iron exporter located on enterocytes, macrophages, hepatocytes, and placental cells. When hepcidin binds ferroportin, ferroportin becomes internalized and degraded. This reduces movement of iron into circulation and increases intracellular iron retention. Because iron can catalyze reactive oxygen species formation when present in excess, hepcidin regulation is critical for balancing nutrient availability with oxidative protection.
Hepcidin is produced primarily by hepatocytes within the liver and encoded by the HAMP gene. It is synthesized initially as preprohepcidin, processed into prohepcidin, and then converted into mature active hepcidin before secretion into blood. The liver serves as the dominant endocrine source controlling whole-body iron balance, although local tissue expression may occur in macrophages and additional tissues under certain conditions.
Hepcidin production integrates information regarding body iron stores, circulating transferrin saturation, oxygen status, erythropoietic activity, inflammation, and hepatic signaling pathways. Iron stored within hepatocytes and macrophages strongly influences expression because long-term iron balance depends on coordinated intestinal absorption and recycling efficiency.
Hepcidin regulation involves several major signaling systems including BMP-SMAD pathways, inflammatory cytokine pathways, erythropoietic signaling, and oxygen-related sensing systems. Bone morphogenetic protein 6 strongly stimulates hepcidin transcription when iron stores are elevated. Hemojuvelin, transferrin receptors, and HFE-related signaling also participate in iron sensing.
Inflammatory signaling, especially interleukin-6 activation through JAK-STAT pathways, markedly increases hepcidin production during immune activation. In contrast, active red blood cell production suppresses hepcidin through erythroferrone signaling from erythroblasts. Low oxygen states and iron deficiency also reduce hepcidin synthesis. Through this integrated regulation, hepcidin coordinates iron absorption, iron recycling, erythropoiesis, oxidative balance, and systemic nutrient distribution.
Liver peptide hormone that lowers iron absorption/release by causing ferroportin internalization.
