Fkbp4, a member of the FK506-binding protein (FKBP) family, also known as FKBP52, is a co-chaperone protein involved in immunoregulation, basic cellular processes like protein folding and trafficking, especially in association with HSP90. It is implicated in multiple signaling pathways relevant to cell metabolism, proliferation, and survival, making it of great biological importance. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

Loss-of-function studies of Fkbp4 have revealed its diverse roles. In hepatocellular carcinoma (HCC), knockdown of Fkbp4 inhibits cell proliferation, migration, and glycolysis, suggesting it promotes HCC development via the p53/HK2 axis [1]. In colon cancer, IMS-localized Fkbp4 is essential for mitochondrial respiration and 5-fluorouracil sensitivity by controlling the assembly of the mitochondrial COA6/SCO1/SCO2 complex [2]. In breast cancer, Fkbp4 expression is associated with disease progression, especially in ER-negative breast cancer, and it activates the PDK1/Akt-dependent cell proliferation signaling by connecting mTORC2 and PI3K [3]. In non-small-cell lung cancer (NSCLC), Fkbp4 promotes cell proliferation, migration, invasion, and tumor growth in vivo by activating the Akt/mTOR signaling pathway [4].

In conclusion, Fkbp4 plays crucial roles in various biological processes and disease conditions. Model-based research, particularly through Fkbp4 KO/CKO mouse models, has provided insights into its functions in cancers such as HCC, colon, breast, and NSCLC. Understanding Fkbp4 can potentially lead to new therapeutic strategies for these malignancies.