Circuits that guarantee iron homeostasis: from cellular sensing to systemic control

Iron is an essential yet potentially toxic element whose redox properties support diverse cellular processes, including oxygen transport, energy metabolism, DNA synthesis, and epigenetic regulation. To maintain iron availability while limiting its toxicity, organisms have evolved sophisticated mechanisms governing its absorption, transport, uptake, utilization, storage, and recycling at both cellular and systemic levels. In vertebrates, cellular iron homeostasis is primarily controlled by the IRE–IRP system, whereas systemic iron balance is governed by the liver-derived hormone hepcidin, which integrates signals reflecting iron stores, circulating iron, and erythropoietic demand. Increasing evidence has revealed additional layers of hepcidin regulation that integrate metabolic, stress, and environmental cues, underscoring the complexity and dynamic nature of systemic iron control. In this review, we provide an updated overview of the mechanisms coordinating cellular and systemic iron homeostasis, from dietary iron absorption and systemic transport to cellular uptake, utilization, storage, and macrophage-mediated recycling. We discuss the molecular pathways governing hepcidin production and the integration of signals reflecting body iron status and physiological demand. We further examine how dysregulation of iron and hepcidin homeostasis contributes to iron-related disorders, including iron deficiency and hemochromatosis, and highlight emerging functions of several iron-regulatory proteins that extend beyond their established roles in iron metabolism.