HepcidinRegulation

HepcidinRegulation refers to the physiological and molecular processes that control production of hepcidin, a liver-derived peptide hormone central to systemic iron homeostasis. Hepcidin regulates iron levels by binding to the cellular iron exporter ferroportin on enterocytes, macrophages and hepatocytes, inducing its internalization and degradation; elevated hepcidin reduces plasma iron by limiting dietary absorption and release from stores, while low hepcidin increases iron availability.

Key regulatory pathways include the bone morphogenetic protein (BMP)/SMAD signaling axis, particularly BMP6 and co-receptors such as hemojuvelin, which stimulate hepcidin transcription in response to iron loading. Inflammatory signals, notably interleukin-6, activate JAK/STAT3 signaling to upregulate hepcidin during infection or chronic inflammation. Conversely, increased erythropoietic demand suppresses hepcidin via erythroferrone produced by developing erythroblasts; hypoxia and anemia also downregulate hepcidin to mobilize iron. Matriptase-2 (TMPRSS6) is a negative regulator that cleaves hemojuvelin, lowering hepcidin expression.

Dysregulation of hepcidin underlies several clinical conditions: inappropriately low hepcidin contributes to hereditary hemochromatosis and iron overload, while persistently high hepcidin is implicated in anemia of chronic disease and iron-refractory iron deficiency anemia. Hepcidin and its pathways are targets for diagnostic assays and therapeutic approaches, including hepcidin agonists, antagonists, and modulators of upstream signaling.