CYB5R3, also known as NADH-cytochrome b5 reductase 3, is an enzyme crucial for maintaining cellular redox homeostasis, regulating the redox state of soluble guanylate cyclase heme iron, and participating in processes like fatty acid synthesis and drug metabolism [1,2,5]. It is associated with pathways such as the ER-phagy, TGF-β1 signaling, and is involved in maintaining the stability of glucokinase for glucose utilization [1,2,3].

In CYB5R3 ufmylation-defective knock-in mice, microcephaly occurs, indicating that CYB5R3 ufmylation-induced ER-phagy is essential for brain development [1]. In AECIIs, deficiency of CYB5R3 leads to sustained TGF-β1 activation and increased lung fibrosis susceptibility [2]. Cyb5r3 β-cell-specific knockout mice phenocopy secondary sulfonylurea failure, highlighting Cyb5r3 as a key factor in this process [3]. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, glucose intolerance, and diet-induced hyperglycemia, revealing its role in β-cell function [4]. Conditional cardiomyocyte-specific CYB5R3-knockout in male mice causes cardiac hypertrophy, bradycardia, and sudden cardiac death, showing its importance in cardiomyocyte redox biology [6].

In conclusion, CYB5R3 plays essential roles in multiple biological processes, including brain development, lung fibrosis prevention, diabetes-related β-cell function, and cardiomyocyte redox equilibrium. Studies using KO/CKO mouse models have significantly contributed to understanding its functions in these disease-related areas, highlighting its potential as a therapeutic target in conditions such as neurological disorders, lung fibrosis, diabetes, and heart failure.