USP48 is a deubiquitinase that removes ubiquitin from target proteins, playing diverse regulatory roles across multiple cellular pathways. It recognizes and hydrolyzes the C-terminal peptide bond of ubiquitin, functioning in both polyubiquitin precursor processing and deubiquitination of ubiquitinated proteins. USP48 regulates NF-κB signaling by deubiquitinating RELA and stabilizes Aurora B to promote cell cycle progression. During H. pylori infection, it stabilizes nuclear RELA to enhance TNFAIP3 synthesis, thereby suppressing apoptosis. USP48 also modulates photoreceptor function by stabilizing retinal proteins ARL3 and UNC119, and positively regulates pyroptosis by stabilizing GSDME through removal of Lys-48-linked ubiquitination. Clinically, USP48 mutations have been identified in pituitary corticotroph tumors causing Cushing syndrome, occurring in less than ~20% of cases 1. Recent studies reveal divergent cancer roles: USP48 expression is downregulated in colorectal cancer, where it suppresses tumorigenesis by stabilizing TAK1 and inhibiting NF-κB activation 2; conversely, in acute myeloid leukemia, caspase-3-mediated cleavage of USP48 during drug-induced apoptosis enhances chemotherapy efficacy 3. USP48 also exacerbates sepsis-induced acute lung injury by promoting macrophage pyroptosis through NEK7-dependent NLRP3 inflammasome activation 4. Additionally, USP48 contributes to clear cell renal cell carcinoma progression by stabilizing SIRT6, promoting lipid metabolic reprogramming 5. USP48 modulates metabolic diseases including diabetic complications 6.