Ubiquitin-specific protease 48: Molecular mechanisms, pathophysiological roles and therapeutic potential

Ubiquitin-specific protease 48 (USP48) is a deubiquitinase (DUB) belonging to the USP subfamily, the largest and functionally most diverse class of DUBs. As a critical post-translational regulator, USP48 governs a wide range of physiological and pathological processes, with well-established and context-dependent roles in tumorigenesis, cancer progression, and therapeutic resistance. Mechanistically, USP48 displays remarkable specificity for distinct lysine-linked ubiquitin chains on substrate proteins, thereby preventing their proteasomal degradation and precisely modulating their subcellular localization and enzymatic activity. This regulatory function orchestrates core cellular programs including the DNA damage response, cell cycle checkpoint control, and tumor immune microenvironment remodeling, through modulation of the MDM2/p53, PI3K/Akt, and NF-κB signaling axes via both catalytic and non-catalytic mechanisms. A defining feature of USP48 is its striking context-dependent functional duality: while it predominantly functions as an oncogenic driver, it exerts tumor suppressor activity in specific tissue and genetic contexts. Emerging studies have further expanded its pathophysiological spectrum to include sorafenib resistance in hepatocellular carcinoma, sepsis-associated acute lung injury, and diabetic microvascular complications. In this review, we systematically synthesize current advances in USP48 structure, substrate specificity, molecular mechanisms, and disease-specific functions, provide a critical evaluation of preclinical USP48-targeted therapeutic strategies, and delineate the major conceptual and translational challenges impeding the clinical development of USP48-based interventions.