Iron regulatory protein 1 (IRP1)

Iron regulatory protein 1 (IRP1) is a bifunctional protein that serves as a central sensor and regulator of cellular iron homeostasis [1, 5]. In iron-replete conditions, IRP1 functions as a cytosolic aconitase (ACO1), utilizing a [4Fe-4S] iron-sulfur cluster to catalyze the conversion of citrate to isocitrate in the citric acid cycle [1, 8]. When cellular iron levels are low or in response to oxidative stress, the iron-sulfur cluster is lost, and the protein undergoes a significant conformational change to its apo-form, which acts as an RNA-binding protein [4, 5]. In this regulatory state, IRP1 binds with high affinity to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding proteins involved in iron uptake (e.g., transferrin receptor 1), storage (e.g., ferritin), and utilization (e.g., HIF2α) [1, 6]. This binding either stabilizes the mRNA or represses its translation, thereby coordinating the cellular response to iron availability [5, 6]. Dysregulation of the IRP1 pathway is implicated in various diseases, including neurodegenerative disorders like Parkinson's and Alzheimer's, where iron-induced oxidative stress and ferroptosis play key roles [2, 15]. It is also associated with certain cancers, such as melanoma, and hematological conditions like anemia [6, 9]. While specific IRP1-targeted therapies are not yet clinically approved, the protein is a major focus for drug discovery efforts aimed at modulating iron metabolism and preventing iron-mediated cell death [2, 7]. Interactions with drugs like doxorubicin can lead to the formation of a 'null' protein state, contributing to side effects such as cardiotoxicity [4].

Other names

Aconitase 1ACO1Iron-responsive element-binding protein 1IRE-BP1Ferritin repressor proteinCitrate hydro-lyasec-aconitase

Post-transcriptional regulation of iron metabolism genes by binding to iron-responsive elements (IREs) in target mRNAs, which either inhibits translation or prevents mRNA degradation depending on the IRE position.