Iron regulatory protein 1 and 2 (IRP1 and IRP2)

Iron Regulatory Proteins 1 and 2 (IRP1 and IRP2) are essential cytosolic RNA-binding proteins that serve as the master regulators of cellular iron metabolism in vertebrates [1, 2]. They function by binding to conserved stem-loop structures known as Iron-Responsive Elements (IREs) located in the untranslated regions (UTRs) of mRNAs that encode proteins for iron uptake, storage, and export [3, 6]. IRP1 is a bifunctional protein; in iron-replete conditions, it binds a [4Fe-4S] cluster and functions as a cytosolic aconitase, whereas in iron-deficient conditions, it loses the cluster and adopts an IRE-binding conformation [1, 11]. IRP2 lacks aconitase activity and is primarily regulated by iron-dependent proteasomal degradation mediated by the E3 ubiquitin ligase FBXL5 [3, 4]. Dysregulation of the IRP/IRE system is linked to several human pathologies, including neurodegenerative disorders like Alzheimer's and Parkinson's diseases, where iron accumulation drives oxidative damage and protein aggregation [6, 12]. In oncology, IRPs play a critical role in modulating ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, making them attractive targets for cancer therapy [7, 14]. Therapeutic interventions include small molecules like Tempol, which can activate IRP1 to mitigate neurodegeneration, and iron chelators that indirectly modulate IRP activity to restore iron balance [4, 6]. Understanding the tissue-specific roles of IRP1 and IRP2 is crucial for developing targeted therapies that avoid systemic toxicity while addressing localized iron dyshomeostasis [5, 10].

Other names

Aconitase 1 (ACO1)Iron-responsive element-binding protein 1 (IREB1)Iron-responsive element-binding protein 2 (IREB2)Ferritin repressor proteinCytosolic aconitaseIRE-BP 1IRE-BP 2

Drugs targeting the IRP system typically act by modulating the labile iron pool (e.g., iron chelators), inducing conformational changes that activate RNA-binding activity (e.g., Tempol), or triggering ferroptosis by increasing IRP-mediated iron uptake and decreasing storage (e.g., erastin and RSL3).