Role of Iron Metabolism in Anemia

Abstract

Anemia remains one of the most prevalent hematological disorders worldwide, affecting nearly two billion individuals. Central to its pathophysiology is iron metabolism, which underpins hemoglobin synthesis, mitochondrial energy production, and diverse enzymatic functions. Because unbound iron catalyzes reactive oxygen species formation, its regulation is tightly controlled through absorption, transport, storage, and recycling. Hepcidin, the master regulator of ferroportin, orchestrates systemic iron balance, and disturbances in this network give rise to distinct clinical phenotypes. Iron deficiency anemia commonly results from inadequate intake or chronic blood loss, whereas anemia of chronic disease reflects inflammatory upregulation of hepcidin. Genetic mutations in iron transport proteins further contribute to hereditary anemias. Recent advances emphasize the roles of hypoxia-inducible factors, erythroferrone, and immune signaling in adjusting iron availability during hypoxia and increased erythropoietic demand. Oxidative stress and ferroptosis exacerbate ineffective erythropoiesis and premature red cell destruction, linking iron imbalance to cellular injury. Macrophage-mediated recycling and hepatic storage normally buffer systemic fluctuations, but these mechanisms are impaired in chronic inflammation, thalassemia, and hemochromatosis. Clinically, precise diagnosis integrates conventional markers such as serum ferritin, transferrin saturation, and soluble transferrin receptor with emerging assays for hepcidin, which help distinguish iron deficiency anemia from anemia of chronic disease. Therapeutic innovation increasingly focuses on modulating hepcidin activity, targeting erythroferrone pathways, and developing safer iron formulations. Collectively, these insights highlight iron metabolism as a mechanistic cornerstone of anemia, bridging molecular regulation, oxidative stress, and biomarker development while guiding strategies for diagnostic accuracy and therapeutic progress