Iron regulatory protein (IRP)

Iron regulatory proteins (IRPs), comprising IRP1 and IRP2, are essential sensors and regulators of intracellular iron homeostasis in mammals. When cellular iron levels are low, IRPs bind with high affinity to conserved RNA stem-loop motifs called Iron Responsive Elements (IREs) located within the untranslated regions of target mRNAs (UniProt P21399, P48200). Binding to the 5' UTR of transcripts such as ferritin and ferroportin inhibits their translation, while binding to the 3' UTR of the transferrin receptor 1 mRNA increases its stability and expression, collectively increasing iron availability (Wilkinson & Pantopoulos, 2014, 'The IRP/IRE system'). Conversely, in iron-replete conditions, IRP1 functions as a cytosolic aconitase and loses its RNA-binding ability, while IRP2 is targeted for proteasomal degradation (Muckenthaler et al., 2017, 'A Red Carpet for Iron Metabolism').\n\nThe IRP system is frequently dysregulated in various diseases, most notably in cancer, where high IRP activity maintains the elevated iron levels necessary for rapid cell proliferation, and in neurodegenerative disorders where iron-mediated oxidative stress contributes to neuronal death (Zhang et al., 2022, 'Iron Regulatory Proteins in Health and Disease'). Consequently, IRPs are emerging as therapeutic targets; for example, small molecules like Tempol have been identified as inhibitors of IRP RNA-binding activity to treat iron-dependent pathologies (Soule et al., 2007, PMID: 17565385). Developing drugs that target IRPs remains challenging because of their fundamental role in systemic iron balance, necessitating strategies that minimize off-target effects on non-target tissues and erythropoiesis.

Other names

Iron-responsive element-binding proteinIRE-BPIron regulatory factorAconitase 1ACO1Iron-responsive element-binding protein 2IREB2Cytosolic aconitase

Iron regulatory proteins control iron metabolism by binding to Iron Responsive Elements (IREs) on target mRNAs; therapeutic agents modulate this interaction either by directly inhibiting RNA binding or by altering IRP protein stability and iron-sulfur cluster assembly, thereby regulating the expression of iron uptake, storage, and export proteins.