Iron is a crucial but potentially toxic biometal essential for various cellular functions, including oxygen transport, energy metabolism, and DNA synthesis. Iron is primarily obtained from the diet through dietary iron absorption in the duodenum, facilitated by transporters like DMT1 and ferroportin. The liver produces hepcidin, a hormone that regulates systemic iron homeostasis by controlling iron efflux from cells via ferroportin. Hepcidin expression is influenced by factors such as BMP signaling, inflammation, and hypoxia. The IRE-IRP system, involving iron-responsive elements (IREs) and iron-regulatory proteins (IRPs), plays a key role in post-transcriptional regulation of genes involved in iron uptake, storage, and utilization. IRP1 and IRP2 can bind to IREs in mRNA untranslated regions, modulating gene expression. IRP1 has both catalytic and IRE-binding activities, while IRP2 primarily functions as an IRE binder. The structure of IRP1 reveals its dual function and the mechanism of IRE binding. Iron-dependent regulation of IRP1 involves the assembly and disassembly of its iron-sulfur clusters (ISCs), which control its activity and stability. This review highlights the complex regulatory mechanisms of cellular iron metabolism and the significance of the IRE-IRP system in maintaining iron homeostasis.Iron is a crucial but potentially toxic biometal essential for various cellular functions, including oxygen transport, energy metabolism, and DNA synthesis. Iron is primarily obtained from the diet through dietary iron absorption in the duodenum, facilitated by transporters like DMT1 and ferroportin. The liver produces hepcidin, a hormone that regulates systemic iron homeostasis by controlling iron efflux from cells via ferroportin. Hepcidin expression is influenced by factors such as BMP signaling, inflammation, and hypoxia. The IRE-IRP system, involving iron-responsive elements (IREs) and iron-regulatory proteins (IRPs), plays a key role in post-transcriptional regulation of genes involved in iron uptake, storage, and utilization. IRP1 and IRP2 can bind to IREs in mRNA untranslated regions, modulating gene expression. IRP1 has both catalytic and IRE-binding activities, while IRP2 primarily functions as an IRE binder. The structure of IRP1 reveals its dual function and the mechanism of IRE binding. Iron-dependent regulation of IRP1 involves the assembly and disassembly of its iron-sulfur clusters (ISCs), which control its activity and stability. This review highlights the complex regulatory mechanisms of cellular iron metabolism and the significance of the IRE-IRP system in maintaining iron homeostasis.