Fkbp4, a member of the FK506-binding protein (FKBP) family, also known as FKBP52, is a co-chaperone protein. It is involved in multiple cellular processes such as protein folding and trafficking associated with HSP90, and has been implicated in immunoregulation. Fkbp4 participates in various signaling pathways including p53/HK2, IKK/NF-κB, and PI3K-Akt-mTOR, highlighting its importance in normal biological functions and disease [1,3,4]. Genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models can be valuable for further exploring its functions.

Loss-of-function studies of Fkbp4 have revealed its significant roles in cancer. 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 (5-FU) sensitivity. Silencing it may affect the assembly of the mitochondrial COA6/SCO1/SCO2 complex [2]. In lung adenocarcinoma, Fkbp4 promotes tumor progression by integrating FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate NF-κB transcriptional activity and nuclear translocation [3]. In breast cancer, depletion of Fkbp4 reduces cell growth and proliferation, especially in triple-negative breast cancer, and it connects mTORC2 and PI3K to activate PDK1/Akt-dependent cell proliferation signaling [4]. 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 [5].

In conclusion, Fkbp4 plays crucial roles in cancer-related biological processes, such as cell proliferation, migration, invasion, and metabolism. Loss-of-function experiments, potentially including KO or CKO mouse models, have been instrumental in uncovering its role in promoting the progression of various cancers, providing potential therapeutic targets for these malignancies [1-3,6,7].