IREB2 encodes iron-responsive element-binding protein 2 (IRP2), an RNA-binding protein that regulates iron homeostasis by binding iron-responsive elements (IREs) in the 5' and 3' untranslated regions of target mRNAs 1. IRP2 represses ferritin mRNA translation while stabilizing transferrin receptor mRNA, thereby controlling intracellular iron levels 2. The protein contains a [4Fe-4S] cluster that enables aconitate hydratase activity and serves as an iron sensor 3. Mechanistically, IREB2 expression and stability are regulated post-translationally; OTUD1 deubiquitinase stabilizes IREB2 to enhance transferrin receptor-mediated iron transport and ferroptosis 4. IREB2 dysfunction has significant clinical relevance. Biallelic IREB2 mutations cause early-onset neurodegeneration with choreoathetoid movements and microcytic anemia; the c.2477 A>T variant increases IRP2 degradation, disrupting iron homeostasis 2. IREB2 polymorphisms (rs2568494) associate with chr15 obstructive pulmonary disease (COPD) susceptibility, with increased IREB2 expression observed in COPD lung tissue 5. Additionally, IREB2 knockdown attenuates ferroptosis-induced anti-tumor effects in lung cancer 6, suggesting potential therapeutic targeting in cancer treatment.