CYB5R3, also known as NADH-cytochrome b5 reductase 3, is an enzyme crucial for maintaining cellular redox homeostasis. It is involved in multiple cellular metabolic processes such as fatty acid synthesis, drug metabolism, and is also a key regulator in pathways like the sGC/cGMP/protein kinase G axis [2,4]. It has significant biological importance in processes from brain development to preventing lung fibrosis [1,2]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In CYB5R3-related research, ufmylation-defective Cyb5r3 knock-in mice exhibit microcephaly, indicating that CYB5R3 ufmylation is indispensable for brain development [1]. CYB5R3-deficient mice in type II alveolar epithelial cells show sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis [2]. β-cell-specific deletion of Cyb5r3 in mice leads to impaired insulin secretion, glucose intolerance, and diet-induced hyperglycemia, revealing its role in pancreatic β-cell function [3]. Loss of cardiomyocyte CYB5R3 in male, but not female, adult mice causes cardiac hypertrophy, bradycardia, and sudden cardiac death, associated with calcium mishandling and oxidative stress [5].

In conclusion, CYB5R3 is essential for maintaining redox balance and normal physiological function in various tissues. Studies using KO/CKO mouse models have revealed its crucial roles in diseases such as microcephaly, lung fibrosis, diabetes, and sudden cardiac death, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Ishimura, Ryosuke, El-Gowily, Afnan H, Noshiro, Daisuke, Noda, Nobuo N, Komatsu, Masaaki. 2022. The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3. In Nature communications, 13, 7857. doi:10.1038/s41467-022-35501-0. https://pubmed.ncbi.nlm.nih.gov/36543799/

2. Bueno, Marta, Calyeca, Jazmin, Khaliullin, Timur, Straub, Adam C, Mora, Ana L. 2023. CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling. In JCI insight, 8, . doi:10.1172/jci.insight.161487. https://pubmed.ncbi.nlm.nih.gov/36749633/

3. Fan, Jason, Du, Wen, Kim-Muller, Ja Young, Cirulli, Vincenzo, Accili, Domenico. 2020. Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure. In Molecular metabolism, 34, 97-111. doi:10.1016/j.molmet.2019.12.008. https://pubmed.ncbi.nlm.nih.gov/32180563/

4. Im, Joo-Young, Kim, Soo Jin, Park, Jong-Lyul, Ban, Hyun Seung, Won, Misun. 2024. CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways. In Experimental & molecular medicine, 56, 235-249. doi:10.1038/s12276-024-01155-9. https://pubmed.ncbi.nlm.nih.gov/38253797/

5. Carew, Nolan T, Schmidt, Heidi M, Yuan, Shuai, Salama, Guy, Straub, Adam C. 2022. Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death. In The Journal of clinical investigation, 132, . doi:10.1172/JCI147120. https://pubmed.ncbi.nlm.nih.gov/36106636/