ACO1 encodes aconitase 1 (also known as iron regulatory protein 1, IRP1), a dual-function protein that serves as a critical regulator of cellular iron homeostasis. Under low iron conditions, ACO1 functions as an RNA-binding protein that binds to iron-responsive elements (IREs) in mRNAs, regulating the translation of iron metabolism proteins 12. When cellular iron levels are high, ACO1 binds a 4Fe-4S cluster and functions as an aconitase enzyme in the citrate cycle, catalyzing the isomerization of citrate to isocitrate. ACO1 plays a significant role in ferroptosis regulation, where its downregulation can sensitize cells to this iron-dependent form of cell death 324. In hepatocellular carcinoma, ENO1 suppresses ACO1 expression by recruiting CNOT6 to accelerate ACO1 mRNA decay, leading to inhibition of mitochondrial iron transport and ferroptosis resistance 2. Genetic variants in ACO1 have major effects on hemoglobin concentration and erythropoiesis, with loss-of-function mutations associated with decreased hemoglobin and increased anemia risk 1. ACO1 expression is frequently altered in various cancers and may serve as a diagnostic biomarker, particularly in diffuse large B-cell lymphoma and thyroid-associated orbitopathy 54.