Advances in iron homeostasis and ferromagnetic nanoparticles

Abstract

The essential trace element iron is a major structural component required for the synthesis and function of hemoglobin and various enzymes, and is therefore involved in many key physiological processes, including oxygen transport, nucleic acid synthesis, gene expression, and immune regulation. Iron homeostasis is therefore essential to maintaining health. For example, iron deficiency leads to anemia, whereas iron overload can lead to the formation of free radicals, which cause lipid peroxidation, DNA damage, and changes in other bioactive molecules. Thus, iron overload has been implicated in a wide range of diseases, including hemochromatosis, diabetes, cardiovascular disease, neurodegeneration, and cancer. Systemically, iron homeostasis is tightly regulated by several processes, including iron absorption in the intestine, iron circulation in the blood, iron utilization in various tissues, iron storage in the liver, and iron recycling in splenic red pulp macrophages. In recent years, new genetic animal models and cutting-edge technologies have led to considerable progress regarding the molecular mechanisms that underlie iron metabolism. Ferroptosis, a recently identified iron-dependent form of cell death, has been implicated in several disease conditions, including acute kidney failure following ischemia/reperfusion, Huntingtons disease, cancer, and neurodegeneration. Although no definitive biomarkers have been identified, lipid peroxidation, PTGS2 expression, and NADPH levels have been suggested as possible biomarkers of ferroptosis. Nevertheless, the regulatory mechanisms underlying ferroptosis are fairly complex and poorly understood. Recently, our understanding of the pathways that regulate hepcidin, the master regulator of iron homeostasis, has increased considerably. Hepcidin regulates systemic iron levels by facilitating degradation of the sole iron exporter, Ferroportin, thereby controlling the absorption, utilization, and storage of iron. Hepcidin also cooperatively regulates iron homeostasis in response to various stimuli; specifically, iron overload and inflammation upregulate hepcidin expression, whereas erythropoiesis and hypoxic stress downregulate hepcidin expression. In addition, several epigenetic processes regulate hepcidin expression, thereby regulating iron metabolism. New studies are continually revealing novel molecular mechanisms related to the complex networks that regulate hepcidin, providing exciting new possibilities for treating iron-related diseases. Iron-containing biological materials have also been studied for their clinical potential. For example, ferromagnetic nanoparticles, which are ferritin- or Fe3O4-containing biomacromolecules, have been applied in a wide variety of biomedical fields due to their superior magnetic properties and biocompatibility, making them ideal drug carriers. Importantly, nanoparticles readily penetrate the blood-brain barrier and enter the central nervous system, improving the bioavailability and therapeutic efficacy of drugs. Alternatively, an external magnetic field can be used to direct ferromagnetic nanoparticles to specific lesions. For example, a drug-containing transferrin nanoparticle complex could be used to targets specific tumor cells due to their increased expression of the transferrin receptor compared to healthy tissue. Superparamagnetic iron oxide nanoparticles may also be a promising tool for destroying cancer cells using a rapidly alternating external magnetic field. Thanks to their wide range of properties and features, ferromagnetic nanoparticles offer a wealth of promising biomedical applications. Here, we review the molecular mechanisms that regulate iron homeostasis, focusing on groundbreaking discoveries in hepcidin regulation and recent progress regarding biomedical applications for ferromagnetic nanoparticles.