Iron regulatory protein-Iron responsive element signaling system (IRP-IRE system) (IRP-IRE system)

The Iron regulatory protein-Iron responsive element (IRP-IRE) signaling system is a central post-transcriptional regulatory network that maintains cellular iron homeostasis (Muckenthaler et al., 2017, Cell). It involves two cytoplasmic RNA-binding proteins, IRP1 (Aconitase 1) and IRP2 (Iron responsive element binding protein 2), which recognize conserved stem-loop structures known as IREs in the untranslated regions of target mRNAs (Anderson et al., 2012, Biochim Biophys Acta). Under conditions of iron deficiency, IRPs bind to IREs to either block the translation of iron-storage proteins like ferritin or stabilize the mRNA of iron-uptake proteins like transferrin receptor 1 (TfR1), thereby increasing intracellular iron availability (Wilkinson & Pantopoulos, 2014, Front Pharmacol). Conversely, high iron levels trigger the conversion of IRP1 into a cytosolic aconitase or the proteasomal degradation of IRP2, facilitating iron storage and preventing toxicity. Dysregulation of this system is linked to diseases such as hereditary hyperferritinemia-cataract syndrome (HHCS), various anemias, and neurodegenerative disorders where iron accumulation promotes oxidative stress (Galy et al., 2013, Blood). Therapeutic interventions targeting the IRP-IRE system, including small molecule inhibitors and antisense oligonucleotides, are being explored for treating cancer and iron-related metabolic disorders (Zhang et al., 2022, Nat Commun).

Other names

IRP/IRE systemIron regulatory protein systemIRP-IRE regulatory networkIron-responsive element-binding protein system

Drugs targeting this system typically act by modulating the binding affinity between Iron Regulatory Proteins (IRP1 and IRP2) and Iron Responsive Elements (IREs) located on target mRNAs, thereby controlling the translation or stability of proteins essential for iron uptake, storage, and export.