CYB5D2, also known as Neuferricin, is a member of the membrane-associated progesterone receptors (MAPRs) family. It binds heme and is involved in multiple cellular processes, such as cell cycle regulation, cholesterol/steroid biosynthesis, drug metabolism, and iron homeostasis [3,5].

In breast cancer, CYB5D2 shows tumor-suppression function. Its down-regulation is associated with cancer progression, as CYB5D2 overexpression induces apoptosis in MCF7 cells while knockdown enhances cell proliferation. Using datasets, CYB5D2 mRNA expression is downregulated in primary breast cancers, and its down-regulation decreases overall survival. A 21-gene signature derived from CYB5D2 is strongly correlated with shortened overall survival and can independently predict breast cancer deaths [1].

In cervical cancer, CYB5D2 also acts as a tumor suppressor. Ectopic expression inhibits HeLa cell invasion and lung metastasis in mice, while knockdown enhances invasion. Two mutations (R7P and R7G) in CYB5D2 abolish its inhibitory effect on HeLa cell invasion, and immunohistochemistry shows CYB5D2 reduction in most cervical squamous cell carcinomas [2].

In hepatocellular carcinoma, CYB5D2 overexpression inhibits cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), and reduces tumor growth in nude mice, suggesting its tumor-suppressor role [4].

In conclusion, CYB5D2 plays a crucial role as a potential tumor suppressor in multiple cancers including breast, cervical, and hepatocellular carcinoma. Functional studies through overexpression and knockdown experiments in cell lines and animal models have revealed its importance in regulating cancer-related cellular processes, providing insights into cancer pathophysiology and potential treatment strategies.