CYB5R3, also known as NADH-cytochrome b5 reductase 3, is an enzyme crucial for maintaining cellular redox homeostasis. It is involved in diverse processes such as fatty acid synthesis, drug metabolism, and regulating the redox state of soluble guanylate cyclase heme iron. It also impacts the intracellular ratio of pyridine nucleotides (NAD⁺/NADH), which is associated with age-related biochemical changes [1,2,4].

In various in vivo studies using KO/CKO mouse models, Cyb5r3 has shown significant implications. In β-cell-specific Cyb5r3 knockout mice, there is impaired insulin secretion, glucose intolerance, and diet-induced hyperglycemia, indicating its role in β-cell function [3]. Cyb5r3-deficient male adult cardiomyocytes in conditional knockout mice lead to cardiac hypertrophy, bradycardia, and sudden cardiac death, revealing its importance in cardiomyocyte redox biology [5]. Ufmylation-defective Cyb5r3 knock-in mice exhibit microcephaly, suggesting its role in brain development through regulation of ER-phagy [1].

In conclusion, Cyb5r3 is essential for maintaining redox balance and is involved in multiple biological processes. The use of KO/CKO mouse models has revealed its significance in diseases like diabetes, heart failure, and developmental disorders, providing valuable insights into the underlying molecular mechanisms and potential therapeutic targets.