USP48 is a deubiquitinating enzyme that removes ubiquitin modifications from target proteins, thereby regulating their stability and function. The enzyme exhibits cysteine-type deubiquitinase activity and localizes to various cellular compartments including the nucleus, cytosol, and mitochondria 1. USP48 plays critical roles in multiple cellular processes through distinct mechanisms. In NF-κB signaling, USP48 stabilizes the transcription factor RelA by counteracting CRL2SOCS1-mediated ubiquitination, which is important for inflammatory responses 1. The enzyme contributes to disease pathogenesis in several contexts: mutations in USP48 are associated with Cushing's disease, found in pituitary corticotroph tumors alongside USP8 mutations 2 3. In sepsis-induced acute lung injury, USP48 exacerbates disease by deubiquitinating and stabilizing NEK7, which promotes NLRP3 inflammasome activation and pyroptotic cell death in alveolar macrophages 4. Conversely, USP48 demonstrates tumor suppressive functions in colorectal cancer by stabilizing TAK1 through deubiquitination, leading to inhibition of NF-κB signaling and promotion of anti-tumorigenic M1 macrophage polarization 5. During apoptosis in acute myeloid leukemia, USP48 is cleaved by caspase-3, and its subsequent degradation enhances drug-induced apoptosis 6. These findings highlight USP48's context-dependent roles in cancer, inflammation, and metabolic disorders.