CYB5R3 (cytochrome b5 reductase 3) is a critical enzyme that catalyzes the NADH-dependent reduction of cytochrome b5, playing essential roles in cellular metabolism and redox homeostasis. The enzyme is involved in multiple metabolic pathways including cholesterol metabolism, where it regulates phospholipid unsaturation and cholesterol excretion through the NRF2/CYB5R3 pathway 1. In pancreatic β cells, CYB5R3 maintains mitochondrial function and insulin secretion through the IL-22RA1/STAT3/c-Jun axis, with deficiency leading to impaired glucose tolerance 2. CYB5R3 also supports glucokinase stability in β cells, and its downregulation contributes to secondary sulfonylurea failure in diabetes 3. The enzyme functions as a tumor suppressor in lung cancer by inducing ER stress-mediated apoptosis through PERK-ATF4 and IRE1α-JNK pathways, with overexpression increasing NAD+ and GSSG production 4. CYB5R3 deficiency causes recessive congenital methemoglobinemia, with pathogenic variants leading to either erythrocyte-restricted (type I) or generalized tissue enzyme deficiency (type II) 56. The enzyme appears crucial for maintaining cellular redox balance and metabolic homeostasis across multiple tissues.