CYLD is a deubiquitinase that specifically cleaves lysine-63 (K63)- and linear (Met-1)-linked polyubiquitin chains, functioning as a critical negative regulator of inflammatory signaling and cell proliferation 1. Primary functions include negatively regulating NF-κB activation by deubiquitinating upstream signaling factors, thereby suppressing inflammation and modulating cell survival and differentiation 23. CYLD removes K63-linked ubiquitin chains from MAP3K7 (TAK1), inhibiting downstream JNK-p38 kinase activation 4, and from MAP3K1/MAP3K3, blocking their interaction with MEK1/2 5. Additionally, CYLD removes linear polyubiquitin from RIPK1 and RIPK2, regulating TNF-induced necroptosis and innate immune responses 67. CYLD also modulates microtubule dynamics by inhibiting HDAC6, promoting α-tubulin acetylation and stabilization 8. In disease contexts, CYLD loss-of-function mutations cause CYLD cutaneous syndrome, characterized by multiple benign head and neck tumors with malignant potential 9. CYLD acts as a tumor suppressor in prostate cancer, promoting ferroptosis through Hippo/YAP pathway regulation 10, and mitigates nonalcoholic steatohepatitis by suppressing hepatic inflammation and fibrosis 4. Conversely, gain-of-function variants associate with neurodegenerative disease 1.