USP2 stabilizes cyclin D1, which participates in homologous recombination (HR)-mediated DNA repair. In numerous cell types, it promotes cell-cycle progression from G1 to S. USP2 becomes active or overexpressed in several cancers, such as mantle cell lymphoma, a subtype of non-Hodgkin’s lymphoma. It has been demonstrated that ML364 (small-molecule USP2 and USP8 inhibitor) induces cell-cycle arrest through cyclin D1 degradation by inhibiting USP2.

In CD4⁺ T cells, USP12 stabilizes B-cell lymphoma/leukemia 10 (BCL10), leading to the activation of the NF-κB signaling pathway. USP12 plays an important role in the differentiation, activation, and proliferation of the CD4⁺ T cell phenotype, but it is not observed in CD8⁺ T cells. According to a recent study, USP12 plays a critical role in prostate cancer through deubiquitination of androgen receptors to increase Ak strain transforming (AKT) signaling. Knockdown of USP12 in HeLa cells leads to cell-cycle arrest and reduced transcription of BMI-1, c-Myc, and cyclin D2; therefore, USP12 may adjust cell-cycle progression (Fu et al., 2021).

USP44 is a significant regulator of the cell cycle, DNA repair, and gene expression. USP44 deficiency in the Emu-Myc mouse B-cell lymphoma model causes early lethality (Lin et al., 2019).

Several key factors have been recognized to play important roles in apoptosis, one of the most important being the tumor suppressor gene p53, and its activity inhibits the generation of tumors. USP2 is described as an oncogene due to its capability to inhibit apoptosis. USP2a has been investigated in numerous cancers, and it has been revealed that higher expression of USP2a is related to advanced stages. In advanced cutaneous T-cell lymphoma (CTCL), the expression of USP2a was lower than that of normal T-lymphocytes, suggesting that it is a tumor suppressor in CTCL, unlike in solid cancers. Wei et al. demonstrated that the knockdown of USP2 causes increased apoptosis after PUVA treatment in MyLa 2000, suggesting that USP2 can display therapeutic resistance. They showed that p53 activation can promote USP2 induction. They also illustrated that USP2 stabilized mouse double minute 2 homolog (Mdm2), but more evidence is needed to link USP2 deubiquitinase activity with Mdm2-p53 signaling. They also explained that USP2 may play an anti-apoptotic role in CTCL and exert a reverse effect in PUVA (Wei et al., 2016).

Kaposi’s sarcoma-associated herpesvirus (KSHV) expresses a series of open reading frames (ORFs) to prevent premature apoptosis and support its viability. Considering that USP7 is a p53 deubiquitinase, KSHV ORF45 inhibits the interactions between USP7 and p53 by binding to p53. As a result, the accumulation and localization of p53 decrease in the cytoplasm, and its transcriptional function decreases.

Under normal circumstances, USP7 binds to human double minute 2 (HDM2) via the death domain-associated protein death-associated protein 6 (DAXX), which prevents the self-ubiquitination of HDM2 and causes the degradation of p53 by HDM2 accumulation. However, in the context of DNA damage, HDM2 dissociates from the USP7–DAXX complex, resulting in self-ubiquitination and subsequent degradation of HDM2, and then USP7 binds to p53 (Alzhanova et al., 2021). USP15 stabilizes MDM2 and regulates p53 function, thus boosting tumor cell survival (Qu et al., 2018).

Based on a recent experiment, USP9X overexpression was found associated with diffuse large B-cell lymphoma (DLBCL) development and progression. USP9X expression was four times greater in malignant cells, including Farage and Pfeiffer cells, than in normal B cells. Inhibition of this USP using siRNA downregulates the expression of Mcl-1 and upregulates the expression of caspase-3, Bak, and cytochrome C; therefore, knockdown of USP9X induces cell apoptosis and decreases cell proliferation in DLBCL (Peng et al., 2020).

Furthermore, USP9X upregulation plays a key role in the formation of mantle cell lymphoma (MCL) via different pathways, including enhanced cell proliferation and cell cycle, inhibition of cell death, and induction of angiogenesis. USP9X is present at high levels in both peripheral blood mononuclear cells (PBMCs) and MCL cells of patients with MCL. Because USP9X affects cell migration and angiogenesis by elevating CCND1-mediated SOX11 expression, USP9X suppression leads to the downregulation of USP9X protein levels in Z-138 and Jeko-1 cell lines and inhibits tumor development in mice in vivo. In addition, USP9X knockdown shortens the duration of the S stage; reduces the expression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), and proliferating cell nuclear antigen (PCNA); and increases P21 protein expression (Huang et al., 2022a).

USP21 was shown to be overexpressed in the DLBCL lymphoid tissue compared with matching healthy tissues and cell lines such as A20 and SU-DHL-4. It increases the growth of DLBCL cells through cysteine 221 (the catalytic site of USP21), but it does not affect cell death. In addition, USP21 participates in the development of lymphoma through the stabilization of enhancer of zeste homolog 2 (EZH2), which is required for generating germinal centers and lymphoma tumors. There is a positive correlation between the elevated expression of USP21 and high mortality in patients; therefore, small interfering RNA (siRNA) knockdown of USP21 and consequent reduction of tumor cell proliferation may be a promising treatment for DLBCL (Ma et al., 2021).

LIM homeobox 2 (LHX2) is an oncogene that promotes malignancy in breast cancer and pancreatic ductal adenocarcinoma. LHX2 adjusts USP18 expression in cancers with poor prognosis. In addition, the reduction of the expression of the immune gene USP18 can decrease the number of activated dendritic cells (aDC), resulting in poor prognosis (Zhao et al., 2021). In addition, a disorder in USP18 expression in Burkitt lymphoma can lead to interferon (IFN)-stimulated gene expression. Therefore, it is likely that USP18 regulates IFN-I-associated immune responses to develop extranodal diffuse large B-cell lymphoma (EN DLBCL) with poor prognosis. The mitogen-activated protein kinase (MAPK) pathway is a possible downstream pathway of USP18 that plays a role in cellular processes such as proliferation, differentiation, and apoptosis. Overall, USP18 plays a potential role via the MAPK pathway and aDCs in EN DLBCL. In addition to USP12, it regulates the MAPK signaling pathway because its knockout leads to impaired MAPK activity in cells (Zhao et al., 2021).

USP7 regulates various activities, including DNA repair, cell cycle progression, protein localization, and apoptosis. USP7 is overexpressed in lymphomas in dogs, and P5091 is an inhibitor that has cytotoxic effects in canine lymphoma and cancer cells. USP7i likely stabilizes the p53 protein and, therefore, may cause apoptosis (Pawlak et al., 2021).

USP44 plays an important role in DNA repair through its DUB catalytic function on the histones H2B and H2A and promotes gene silencing. USP44 deficiency and overexpression are prone to errors in chromosome separation, aneuploidy, and cancer; for example, its overexpression was noted in T-cell acute lymphoblastic leukemia (Lin et al., 2019). USP34 expression increases in the germinal center B-cell-like (GCB) subtype of DLBCL cases, and USP34 is correlated with Wnt signaling activation by destabilization of β-catenin. In addition, USP34 responds to DNA damage and is a downstream target of mutant ataxia telangiectasia in DNA damage (Li et al., 2018).

UBP43, also known as USP18, is encoded by an interferon-stimulated gene (ISG) and functions as a remover of the ISG15 polypeptide from ISGylated proteins. This protease negatively regulates IFN-I signaling by blocking STAT phosphorylation, leading to a reduction in the induction of ISGs. This inhibition occurs via the direct displacement of Janus kinase 1 (JAK1) from the IFN-α/β receptor. A reduction in the IFN-inducible expression of UBP43 leads to a notable delay in the negative feedback regulation of type-I interferon signaling in Burkitt lymphoma (BL) cell lines (including Akata A.2 and A.15), regardless of their Epstein–Barr virus (EBV) status (Ruf et al., 2009).

The use of drugs that inhibit proteasome (mainly bortezomib) activity in multiple myeloma is currently a standard therapy. One way of targeting the proteasome is through USPs such as USP14 for different cancer types, including lymphoma, and even cancer cells resistant to bortezomib (Delforoush et al., 2017).

USP24 has anti-apoptotic tumoral activity in myeloma cells and is overexpressed in drug-resistant cells. It was also found that enhanced USP24 expression was regularly observed in the interfollicular zones of splenic marginal zone lymphoma (SMZL) patients. Given its role in regulating tumor microenvironment signaling, USP24 has been identified as a potential therapeutic target (Robinson et al., 2020).

USP1 can act as an oncogene and is highly expressed in DLBCL patients. High expression of USP1 is associated with poor prognosis in DLBCL. USP1 plays an important role in the rituximab/chemotherapy resistance of DLBCL via deubiquitination of MAX (highly expressed in DLBCL cells). Knockdown of USP1 leads to inhibition of cell proliferation, cell-cycle arrest, reduced MAX/MYC, and autophagy in DLBCL cells (Li et al., 2023).

Some members of the USP family are considered possible targets of anticancer agents, such as USP7, which targets c-Myc. USP7 inhibition destabilizes the CHK1 protein, resulting in AML cells being sensitized to the chemotherapeutic factor cytarabine. Targeting USP1 may also be another therapeutic strategy for MYC-related tumors. Eµ-Myc/cRel^−/− lymphomas have downregulated the expression of USP1 and checkpoint kinase 1 (CHK1) protein that results in resistance to treatment by specific CHK1i. The loss of the CHK1 pathway is related to the downregulation of CHK1, and USP1 inhibition with ML323 can contribute to CHK1 inhibitor resistance (Hunter et al., 2022b).

USP39 elimination in the B-cell lineage prevented the transition from pre-pro-B cells to pro-B cells in the bone marrow, resulting in substantial reduction in mature B cells in peripheral tissues. USP39 ablation in Em-Myc mice successfully controls the expansion of malignant pre-B cells, lowered B-cell lymphomagenesis, and boosted survival. Because the spliceosome component of USP39 has a role in B-cell development and in controlling the rearrangement of immunoglobulin genes, targeting USP39 could represent a promising therapeutic strategy for treating B-cell lymphoma (Ruan et al., 2022).

USP37 expression is positively associated with c-MYC expression in activated B-cell-like-DLBCL (ABC-DLBCL) but not with its GCB subtype. USP37 stabilizes c-MYC and causes unusual cell growth. USP22 and USP36 regulate the cellular turnover of c-MYC in breast cancer, and c-MYC expression is stabilized by USP28 and USP37 in colon carcinoma and lung cancer, respectively. Other USPs, including USP13, USP16, USP17, and USP22, can maintain c-MYC expression in the GCB subtype of DLBCL (Kamran et al., 2023).

Viruses such as Kaposi’s sarcoma-associated herpesvirus (KSHV) control deubiquitination. KSHV is the causative agent of Kaposi’s sarcoma, primal effusion lymphoma, and the plasmablastic shape of multicentric Castleman disease. Here, USP9X plays a pro-viral role, and its depletion prevents virus reactivation and the production of infectious virions (Chappell et al., 2023).

USP29 stabilizes MYC and hypoxia-inducible factor 1-alpha (HIF1α); therefore, it enables tumor cells to respond to both normoxia and hypoxia. Knockout of Usp29 significantly prolongs the survival of tumor-bearing mice by reducing the expressions of MYC and HIF1α in neuroblastoma and B-cell lymphoma. Therefore, USP29 can be used as a new therapeutic target for treating cancer (Tu et al., 2021).

USP7 expression was significantly increased in three cancer types, including DLBCL. ABC-DLBCL is a subtype of non-Hodgkin’s lymphoma with a poor prognosis; its survival is related to the activation of BCR signaling. USP7 stabilizes WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia 2 (MLL2) (parts of lysine-specific methyltransferase complex) in ABC-DLBCL cells. The expression of USP7 is upregulated in ABC-DLBCL cells and downregulated in GCB-DLBCL cells; therefore, USP7 inhibition has a serious effect on ABC-DLBCL cells, contrary to that observed in GCB-DLBCL cells. ABC-DLBCL cells upregulate the expression of some components of BCR signaling, and USP7 inhibition decreases the expression of upregulated parts of BCR signaling and plays an important role in therapeutic targets (Wu et al., 2022a).

Latent membrane protein 1 (LMP1) is expressed in EBV-associated lymphomas. USP2a is detected in LMP1-positive Burkitt’s lymphoma (BL) cells and mediates the stabilization of fatty acid synthase (FASN). FASN expression is notably correlated with distant lymph node metastasis. USP2a inhibition through ML364 decreased FASN levels and inhibited the proliferation of LMP1-positive BL cell lines. Targeting USP2a is an effective strategy for future investigation of ML364 treatment in malignancies with LMP1-positive expression (Hulse et al., 2021).

The fact that we only considered three databases (PubMed, Web of Science, and Scopus) may prove to be a limitation to our study. In addition, the exclusion of studies published in other languages may constitute another limitation of our study.