CYB5R2 (cytochrome b5 reductase 2) is a membrane-bound enzyme that catalyzes NADH-dependent reduction reactions and plays crucial roles in cellular metabolism and disease pathogenesis. The protein functions as a key regulator of iron homeostasis and ferroptosis, with CYB5R2-mediated iron reduction being essential for iron-dependent cell death pathways 1. In cancer biology, CYB5R2 exhibits tumor suppressor properties by inhibiting angiogenesis through downregulation of VEGF expression and modulation of angiogenesis-related genes 2. CYB5R2 expression is epigenetically regulated and serves as a prognostic marker in glioblastoma, where hypomethylation and overexpression correlate with poor patient survival 3. In diabetic retinopathy, CYB5R2 functions as a protective factor against pathological angiogenesis and inflammation, with its expression being regulated by non-coding RNA networks including MEG3/miR-6720-5p and hsa_circ_0000047/miR-6720-5p axes 45. The enzyme also plays a role in drug resistance mechanisms, where transcriptional silencing by ATF7IP contributes to sorafenib resistance in hepatocellular carcinoma by inhibiting ferroptosis 6. Additionally, CYB5R2 shows population-specific genetic variants in Arctic peoples related to lipid metabolism adaptation 7.