USP18 (ubiquitin specific peptidase 18) is a deubiquitinating enzyme that functions as both an ISG15-specific protease and a negative regulator of type I interferon signaling. The protein serves as a major deISGylation enzyme for nuclear proteins and plays crucial roles in antiviral immunity 1. USP18 exhibits dual functions in immune regulation: it positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS, acting as a scaffold protein to facilitate TRIM31 relocalization and enhance MAVS-mediated antiviral signaling 2. Conversely, USP18 functions as a negative regulator by controlling the enhancer landscape of cells and diminishing STAT2-mediated transcription complex binding to interferon-responsive elements 3. The enzyme regulates STING activity through ISGylation, with STING ISGylation at K289 being crucial for oligomerization and type I interferon induction 4. USP18 also stabilizes SLC7A11, a cystine transporter involved in ferroptosis regulation 5. In disease contexts, USP18 is implicated in autoimmune diseases like systemic lupus erythematosus and primary Sjögren's syndrome 6, and paradoxically enhances HIV-1 replication by abrogating antiviral functions of p21 and SAMHD1 7. Lower USP18 expression correlates with better cancer survival, as its depletion promotes cancer cell pyroptosis 3.