CYB5R4, also known as cytochrome b5 reductase 4, is an orphan reductase that serves as an evolutionarily conserved activator of PP4 and PP6 among serine/threonine phosphoprotein phosphatases (PPPs), crucial for intracellular signaling in eukaryotes. Heme binding by CYB5R4 is essential for its function, which mechanistically involves the reduction of metal ions in the active site of PP4 and PP6 [6].

In podocytes, siRNA silencing of CYB5R4 led to significant downregulation of CD2AP and synaptopodin, expanding the list of genes essential for podocyte cytoskeletons [1]. In infertile men, CYB5R4 was among the genes remarkably under-expressed, suggesting its potential role in processes related to gametogenesis, fertilization, and embryo development [2]. In Jiaxian Red cattle and Bohai Black cattle, CYB5R4 was identified in genomic regions associated with meat quality traits and fat deposition respectively [3,4]. In Japanese Black cattle, CYB5R4 was selected as a candidate gene for a QTL related to oleic acid percentage [5]. In a chicken F2 crossbred population, CYB5R4 was associated with fatty acid composition in breast meat [7].

In conclusion, CYB5R4 plays essential roles in multiple biological processes, from cell-specific functions in podocytes to being associated with traits in various livestock species related to reproduction and meat quality. Functional studies, such as those using siRNA silencing in podocytes, have revealed its significance in maintaining cellular structures and functions, which could potentially have implications for understanding related diseases and improving livestock breeding.