CYLD, short for CYLD lysine 63 deubiquitinase, is a ubiquitin hydrolase with crucial roles in immunity and cancer. It is a key regulator of diverse cellular processes like immune responses, inflammation, cell death, proliferation, and cell cycle progression [1,5]. CYLD exerts its functions mainly through regulating cellular pathways such as the NF-κB, Wnt, TGF-β, and MAPK pathways [1,5]. Research on CYLD in various model systems, including gene knockout models, has provided valuable insights into its functions [1].

Complete CYLD ablation, truncation, and expression of alternate isoforms lead to distinct phenotypes. For example, in prostate cancer, CYLD acts as a tumor suppressor, inhibiting cell proliferation and enhancing sensitivity to ferroptosis through the Hippo/YAP signaling pathway [2]. In human papillomavirus-associated head and neck cancers, loss-of-function CYLD alterations promote tumorigenesis and malignant transformation by aberrantly activating the NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases pathways [3]. In glioblastoma stem cells, FOSL1 promotes the proneural-to-mesenchymal transition via UBC9-dependent CYLD SUMOylation and subsequent NF-κB activation [4]. In nasopharyngeal carcinoma, CYLD promotes radiosensitivity by inducing high oxidative stress and DNA damage through class I HDACs [6].

In conclusion, CYLD is a multifunctional deubiquitinase that plays essential roles in multiple biological processes and is involved in various diseases, especially cancers. Studies using CYLD gene knockout or conditional knockout mouse models have significantly contributed to understanding its role in disease-related biological processes, offering potential therapeutic targets for treating associated diseases [1-7].