Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease

Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed ‘ferroptosis’, the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.

TrendsDysregulation of iron metabolism contributes to various human pathologies, including iron overload diseases and cancer.Several new proteins have been identified as crucial iron traffickers and chaperones with important connections to human health.Ferroptosis is a unique cell death pathway that is iron-dependent, non-apoptotic, non-necroptotic, and non-autophagic.Dysregulation of the ferroportin/hepcidin regulatory axis contributes to tumor progression and is predictive of patient outcomes.New iron chelators utilize more specific mechanisms to elicit anticancer activity.