OTULIN is a deubiquitinating enzyme that specifically cleaves linear (Met1-linked) polyubiquitin chains and serves as a critical negative regulator of inflammation and immune signaling 12. The protein functions primarily by regulating the linear ubiquitin chain assembly complex (LUBAC), removing Met1-linked autoubiquitination to prevent LUBAC inactivation and maintain immune homeostasis 2. OTULIN acts as a negative regulator of NF-κB signaling by controlling LUBAC activity, thereby restricting spontaneous inflammation 2. Beyond immune regulation, OTULIN plays roles in autophagy by cooperating with LUBAC to regulate autophagy initiation and maturation through ATG13 stabilization 3. The protein also exhibits ubiquitin-independent functions, including interference with endosome-to-plasma membrane trafficking 1. Disease-wise, OTULIN mutations cause severe autoinflammatory conditions: biallelic loss-of-function mutations lead to OTULIN-related autoinflammatory syndrome (ORAS), while monoallelic mutations cause immunodeficiency with susceptibility to invasive Staphylococcal infections 45. In cancer, OTULIN overexpression contributes to chemotherapy resistance in osteosarcoma by stabilizing GPX4 protein and blocking mitochondrial apoptosis 6. Current treatments for OTULIN deficiency involve TNF-blocking agents targeting the dysregulated immune response 5.