Aug 2026· Biochimica et biophysica acta. Reviews on cancer· pp.
189689
· 0 citations· 114 references
Medicine
TL;DR
This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword, and comprehensively evaluates the landscape of emerging USP2 inhibitors.
Abstract
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
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.
Hu Lei, Chujiao Zhu, Li Yang et al.· Biochemical and Biophysical...· 0 citations
By critically appraising its substrate diversity and functional versatility, it is proposed that FBXO11 be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Yuqi Zhang, Changyi Fan, Shiheng Chen et al.· Cancer Science· 0 citations
Deubiquitinases regulate key oncogenic and immune pathways but have proven challenging to exploit therapeutically. Among them, ubiquitin-specific protease 22 (USP22) has emerged as a molecule of interest due to its involvement in both tumor-intrinsic programs and tumor-immune interactions. In this review, we synthesize current evidence describing how USP22 modulates oncogenic transcriptional states and immune evasion. Tumor-intrinsically, USP22 has been implicated in stabilizing select oncogenic factors and shaping chromatin accessibility in ways that can reinforce proliferation, survival, stem-like properties, and metastatic potential. In parallel, USP22 influences antitumor immunity by modulating MHC-I-mediated antigen presentation, immune checkpoint expression, and the fitness of intratumoral regulatory T cells. We discuss emerging pharmacological approaches to target USP22, the limitations of current inhibitor strategies, and the importance of distinguishing direct enzymatic functions from indirect transcriptional consequences. Together, these insights suggest that USP22 inhibition may offer a therapeutic strategy with dual effects on tumor biology and antitumor immunity.
Deyu Fang· Trends in Molecular Medicine· 0 citations
How NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress is examined.
Bo Xiang, Tao Liu, Duo Xu et al.· Frontiers in Physiology· 0 citations
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