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Last update 08 May 2025

USP5

Last update 08 May 2025

Basic Info

Synonyms

Deubiquitinating enzyme 5, isopeptidase T, IsoT

+ [6]

Introduction

Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.

Drugs associated with USP5

SE486-11+SAHA (Children's Cancer Institute)

Target

HDACs x USP5 x c-Myc

Mechanism

HDAC inhibitors [+2]

Active Org.

Children's Cancer Institute Australia

Originator Org.

Children's Cancer Institute Australia

Active Indication

Neuroblastoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CN117865967

Patent Mining

Target

USP5

Mechanism

USP inhibitors [+1]

Active Org.

Tianjin Jiangxinzhicheng Technology Co., Ltd.

Originator Org.

Tianjin Jiangxinzhicheng Technology Co., Ltd.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with USP5

100 Translational Medicine associated with USP5

0 Patents (Medical) associated with USP5

205

Literatures (Medical) associated with USP5

01 May 2025·International Journal of Biological Macromolecules

PDK1-mediated phosphorylation of USP5 modulates NF-κB signalling to enhance osteosarcoma growth

Article

Author: Teng, Junyan ; Zhang, Huijun ; Wang, Fu ; Yu, Zhidan ; Yu, Yin ; Yang, Zhaojie ; Yanzhang, Ruoping ; Jin, Guoguo

The overexpression of pyruvate dehydrogenase kinase 1 (PDK1) has been observed in a number of different cancers, making it a potential target for the treatment of cancer. In this study, we used bioinformatics methods to analyse the immunophenotype of osteosarcoma (OS) and identified PDK1 as a critical factor in the different immune states of the disease. A pan-cancer analysis revealed a robust correlation between PDK1 and the tumour microenvironment. Moreover, our findings corroborate the overexpression of PDK1 in OS, whereby it facilitates tumour development via the NF-κB pathway. From a mechanistic perspective, PDK1 has the capacity to bind and phosphorylate USP5. The phosphorylation of USP5 by PDK1 activates its deubiquitinating activity, leading to the stabilisation of IKKγ protein and subsequent activation of the NF-κB signalling pathway, which ultimately promotes the growth of OS cells. Molecular simulation docking, pull-down assays, and SIP experiments were employed to further identify arctigenin (ATG) as a small molecule inhibitor of PDK1. The findings demonstrated that ATG effectively inhibited the growth of OS cells and tumour xenograft models. Collectively, these results highlight that PDK1 influences NF-κB in OS through the PDK1-USP5-IKKγ axis. Furthermore, the identification of ATG as an effective inhibitor of PDK1 suggests that ATG may serve as a promising lead compound for the treatment of OS.

01 Mar 2025·Cancer Medicine

USP5 Promotes Head and Neck Squamous Cell Carcinoma Progression via mTOR Signaling Pathway

Article

Author: Wang, Yue ; Jiang, Junhong ; Xiong, Ni

ABSTRACTBackgroundHead and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by limited prognostic markers and treatment options, contributing to high mortality rates. While Ubiquitin‐specific peptidase 5 (USP5) has been implicated in various cancers, its role in HNSCC remains poorly understood.AimsThis study aims to investigate the role of USP5 in the progression of HNSCC and explore its potential as both a prognostic biomarker and a therapeutic target.Materials & MethodsThis work utilized single‐cell transcriptomic analysis with the Scissor algorithm to identify distinct epithelial subpopulations, particularly focusing on the Stress subpopulation that exhibited significant upregulation of USP5. Validation was conducted using tissue microarray (TMA) analysis and immunohistochemistry (IHC) to compare USP5 expression levels in HNSCC tissues versus adjacent normal tissues. Furthermore, RNA interference (RNAi) experiments were performed to knock down USP5 expression, assessing its effects on tumor cell behavior, including proliferation, migration, and invasion, as well as the regulation of mTORC1 and NF‐κB signaling pathways.ResultsThis study revealed that the Stress subpopulation, characterized by USP5 upregulation, was associated with enhanced tumor cell proliferation, migration, and invasion. TMA and IHC analyses confirmed that USP5 expression was significantly higher in HNSCC tissues compared to normal tissues, correlating with poor patient prognosis. Additionally, RNAi‐mediated knockdown of USP5 led to reduced tumor cell activities and downregulation of the mTORC1 and NF‐κB signaling pathways.DiscussionThe findings suggest that USP5 plays a critical role in driving HNSCC progression. Its overexpression in aggressive tumor subpopulations and association with poor clinical outcomes highlight its potential utility as both a prognostic biomarker and a therapeutic target. The observed effects on cell behavior and oncogenic signaling pathways provide mechanistic insights into how USP5 for HNSCC therapy.ConclusionsThis study establishes USP5 as a key driver of HNSCC progression, underscoring its potential role in prognosis and therapy. Targeting USP5 may offer novel treatment strategies for HNSCC, addressing the urgent need for effective therapeutic interventions in this aggressive malignancy.

10 Feb 2025·Theranostics

TFEB promotes Ginkgetin-induced ferroptosis via TRIM25 mediated GPX4 lysosomal degradation in EGFR wide-type lung adenocarcinoma

Article

Author: Miao, Xiu-Yuan ; Zhao, Li-Ping ; Dong, Ling-Feng ; Guan, Zhen-Rong ; Yu, Li-Hua ; Tang, Xiao-Qi ; Zhang, Yu-Wen ; Ding, Li-Li ; Lou, Jian-Shu ; Jiang, Ya-Ping ; Yan, Ya-Xin ; Wang, Hao-Jie

Rationale: TFEB activation is associated with prolonged survival in LUAD patients, suggesting potential benefits of TFEB agonists in LUAD treatment. In this study, we identify ginkgetin (GK), derived from Ginkgo folium, as a natural TFEB agonist, which has demonstrated promising anticancer effects in our previous research. TFEB activation has been shown to promote GPX4 degradation, inducing ferroptosis; however, the specific E3 ligases, deubiquitinating enzymes (DUBs), and types of polyubiquitination chains involved remain unclear. The unique mechanisms associated with natural compounds like GK may help elucidate the underlying biological processes. Here, we describe a novel biological event involved in the lysosomal degradation of GPX4 induced by TFEB activation through the utilization of GK. Methods: TFEB activation was induced with GK, and TFEB knockout cells were generated using CRISPR-Cas9. The activity of TFEB and its relationship with ferroptosis were assessed by immunoprecipitation, labile iron pool and lysosomal activity assays. The types of polyubiquitination chains, E3 ligases, and DUBs involved in GPX4 degradation were analyzed using LC-MS, immunoprecipitation, and immunofluorescence. These findings were further validated in an orthotopic xenograft SCID mouse model. Results: GK binds to and activates TFEB, leading to TFEB-mediated lysosomal activation and GPX4 degradation, which induces ferroptosis in LUAD cells. These effects were impaired in TFEB knockout cells. Mechanistically, K48-linked polyubiquitination of GPX4 was required for GK induced GPX4 lysosomal translocation. TFEB knockout reduced both K48-linked ubiquitination and lysosomal translocation of GPX4. Additionally, GK promotes the binding of TFEB and TRIM25. TRIM25 and USP5 were found to competitively bind to GPX4, with TFEB activation favoring TRIM25 binding to GPX4 and reducing the interaction of USP5 and GPX4. These findings were confirmed in a xenograft SCID mouse model using TFEB knockout LUAD cells. Conclusion: This study identifies, for the first time, GK as a promising TFEB agonist for LUAD treatment. TFEB activation promotes TRIM25-mediated K48-linked polyubiquitination and lysosomal degradation of GPX4, driving ferroptosis. This ferroptosis-driven mechanism offers a novel strategy to enhance ferroptosis-based anti-LUAD therapies.

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