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BRCA1-associated protein 1 (BAP1) is a deubiquitinase (DUB) localized in both the nucleus and cytoplasm and is widely recognized as a tumor suppressor. Germline and somatic alterations in BAP1 have been strongly associated with increased susceptibility to diverse cancer types and with adverse clinical outcomes. Although BAP1 is best known for its role in epigenetic regulation, particularly through the modulation of histone H2A monoubiquitination (H2Aub) and gene transcription, accumulating evidence suggests that its functional repertoire extends well beyond these canonical activities. BAP1 is increasingly viewed as a central molecular hub through which fundamental cellular processes are integrated and coordinated via its catalytic activity and dynamic protein interaction networks. In this review, the pleiotropic functions of BAP1 are systematically examined across several biological dimensions, including epigenetic regulation, genomic stability, cellular metabolism, and cell fate determination. Notably, BAP1-mediated regulation is highly context dependent, as cell type, differentiation status and tumor microenvironmental (TME) cues may shape its downstream effects and contribute to heterogeneous biological outcomes. By synthesizing these multidimensional regulatory mechanisms, this review provides an integrated overview of the molecular features and functional roles of BAP1, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis. Collectively, these insights underscore the evolving understanding of BAP1 biology over the past decade and highlight the need for renewed attention to this critical tumor suppressor and its therapeutic potential in cancer.

Understanding the mechanisms underlying metastasis in hepatocellular carcinoma (HCC) is crucial for developing new therapies against this fatal disease. Deubiquitinase ubiquitin‐specific protease 11 (USP11) belongs to the deubiquitinating family and has previously been reported to play a critical role in cancer pathogenesis. Although it has been established that USP11 can facilitate the metastasis and proliferation ability of HCC, the underlying regulatory mechanisms are poorly understood. The primary objective of this research was to reveal hitherto undocumented functions of USP11 during HCC progression, especially those related to metabolism. Under hypoxic conditions, USP11 was found to significantly impact the glycolysis of HCC cells, as demonstrated through various techniques, including RNA‐Seq, migration and colony formation assays, EdU and co‐immunoprecipitation. Interestingly, we found that USP11 interacted with the HIF‐1α complex and maintained HIF‐1α protein stability by removing ubiquitin. Moreover, USP11/HIF‐1α could promote glycolysis through the PDK1 and LDHA pathways. In general, our results demonstrate that USP11 promotes HCC proliferation and metastasis through HIF‐1α/LDHA‐induced glycolysis, providing new insights and the experimental basis for developing new treatments for this patient population.

Legionella pneumophila causes a severe pneumonia known as Legionnaires’ disease. During the infection, Legionella injects more than 300 effector proteins into host cells. Among them are enzymes involved in altering the host-ubiquitination system. Here, we identified two L egionella OT U (ovarian tumor)-like deubiquitinases (LOT-DUBs; LotB [Lpg1621/Ceg23] and LotC [Lpg2529]). The crystal structure of the LotC catalytic core (LotC 14-310 ) was determined at 2.4 Å. Unlike the classical OTU-family, the LOT-family shows an extended helical lobe between the Cys-loop and the variable loop, which defines them as a unique class of OTU-DUBs. LotB has an additional ubiquitin-binding site (S1’), which enables the specific cleavage of Lys63-linked polyubiquitin chains. By contrast, LotC only contains the S1 site and cleaves different species of ubiquitin chains. MS analysis of LotB and LotC identified different categories of host-interacting proteins and substrates. Together, our results provide new structural insights into bacterial OTU-DUBs and indicate distinct roles in host–pathogen interactions.

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1−5 μM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg -1 ·d -1 , intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.

Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination system components, E3 ubiquitin ligases and deubiquitinases have the most prominent roles in modulating tumor metastasis. This review will briefly summarize the observations and underlying mechanisms of multiple E3 ubiquitin ligases and deubiquitinases to regulate tumor metastasis. Further, we will discuss the relationship and importance between ubiquitination components and tumor progression.

Ovarian cancer is a lethal disease due to late diagnosis and occurrence of drug resistance that limits the efficacy of platinum-based therapy. Drug resistance mechanisms include both tumor intrinsic and tumor microenvironment-related factors. A role for deubiquitinases (DUBs) is starting to emerge in ovarian cancer. DUBs are a large family of enzymes that remove ubiquitin from target proteins and participate in processes affecting drug resistance such as DNA damage repair and apoptosis. Besides, DUBs modulate the functions of T cell populations favoring an immune suppressed microenvironment. Three DUBs are proteasome-associated, whereas the large majority are not. Among the former DUBs, USP14 has been proposed to modulate transcription factors such as Bcl6 and BACH1. In addition, RPN11/PSMD14 interferes with various processes including epithelial mesenchymal transition, also favored by non-proteasomal DUBs such as USP1 by acting on Snail. Besides, USP8 by stabilizing HER family receptors can confer drug resistance. Overall, DUBs appear to be druggable, with several inhibitors under development. Based on DUBs biological role, DUBs targeting appears promising in view of combination strategies involving different therapeutic approaches. Here, we summarize the relevance of DUBs in ovarian carcinoma and provide insights into future challenges for the treatment of this disease.

Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.

SummaryThis phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570’s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

USP19 is an important member of the ubiquitin-specific protease (USP) subfamily within the deubiquitinase superfamily. It primarily regulates protein stability, subcellular localization, and signaling pathway activity by specifically removing ubiquitin modifications from substrate proteins, and it is widely involved in the regulation of cellular physiological homeostasis and various pathological processes. USP19 shows aberrant expression and functional dysregulation in multiple malignancies, participating in the regulation of tumor proliferation, metastasis, apoptosis, immune evasion, and chemoresistance by targeting key molecules such as c-Myc, p53, PD-L1, MGMT, and PARK7. Additionally, it regulates inflammatory responses, immune responses, viral infections, and non-neoplastic diseases such as liver injury, fibrosis, and neurodegeneration. Mechanistic research on USP19 has expanded considerably, and its key substrates and signaling pathways have become potential targets for pharmacological intervention; small-molecule modulators and the development of targeted strategies remain at the preclinical stage. USP19 displays disease-specific expression patterns across different tissues: it is aberrantly overexpressed in most tumors and is closely associated with poor patient prognosis, whereas in certain tumors and non-neoplastic diseases it shows low expression or a protective upregulation. This article systematically summarizes the molecular characteristics, physiological functions, disease-related mechanisms, and clinical translational potential of USP19, to provide a comprehensive overview for its use as a novel diagnostic biomarker, prognostic stratification tool, treatment response predictor, and direct drug target.