The NEDD4 family member Smurf2 has well-defined functions across multiple tumor types (33, 34), with particularly prominent roles in RCC. Smurf2 exhibits dual substrate specificity in RCC. Recent studies in ccRCC demonstrate that its high expression negatively correlates with TGF-β receptor II (TbR-II) protein levels, downregulating TGF-β signaling via ubiquitination-mediated degradation of TbR-II (35). In VHL-deficient models, CDK4/6 inhibitors stabilize Smurf2, enabling it to degrade HIF-1α (Hypoxia-Inducible Factor 1-alpha) under normoxic conditions, thereby establishing a VHL-independent negative feedback circuit. Clinically, high Smurf2 expression significantly correlates with prolonged disease-free survival (DFS) and overall survival (OS) in ccRCC patients (36). Collectively, Smurf2 modulates RCC progression through dual mechanisms targeting TbR-II and HIF-1α. However, the ubiquitin chain type preference for these two substrates and the precise details of their reversible regulation remain to be elucidated.

NEDD4 family E3 ligases are generally downregulated in renal carcinoma, with NEDD4L (NEDD4-like) showing the most significant reduction (37). NEDD4L expression is subject to multi-layered suppression in kidney cancer, with RNA-binding protein KSRP serving as the key regulator. In ccRCC, KSRP coordinately inhibits NEDD4L through transcriptional and post-transcriptional mechanisms: on one hand, it induces WT1-mediated transcriptional repression; on the other hand, it upregulates miR-629-5p and directly binds to AU-rich elements to promote mRNA degradation. This results in NEDD4L downregulation and aberrant activation of the PI3K/AKT pathway, ultimately driving tumor proliferation, metastasis, and epithelial-mesenchymal transition (38). In RCC, low NEDD4L expression compromises its ability to suppress proliferation and autophagy while promoting apoptosis through multi-substrate ubiquitination. In clear cell RCC (ccRCC), studies have demonstrated that low NEDD4L expression inversely correlates with RAC2 (Rac family small GTPase 2) levels and associates with shortened overall survival and disease-specific survival. Mechanistically, NEDD4L binds to the Thr108-Pro motif of RAC2 and catalyzes K48-linked ubiquitination and degradation, thereby inhibiting proliferation and inducing apoptosis (39). Additionally, research has reported low NEDD4L expression in ccRCC, where it mediates ubiquitination and degradation of ERBB3 (Erythroblastic Leukemia Viral Oncogene Homolog 3), consequently suppressing MAPK signaling (40) NEDD4L has also been implicated in regulating ULK1 degradation during autophagy (41, 42). Under nutrient deprivation, NEDD4L promotes ULK1 ubiquitination and degradation to prevent excessive autophagy; conversely, NEDD4L knockdown enhances autophagy. Together, NEDD4L’s “low expression–multi-substrate” pattern offers a novel prognostic biomarker panel for ccRCC.

HERC1 and HERC2, as HECT family E3 ubiquitin ligases, influence cell proliferation by regulating signaling pathways. For instance, HERC1 catalyzes K48-linked polyubiquitination of C-RAF (RAF Proto-Oncogene Serine/Threonine-Protein Kinase), promoting its degradation; HERC1 knockdown stabilizes C-RAF, increases ERK phosphorylation, and accelerates cell proliferation. In vitro ubiquitination assays further validate C-RAF as a HERC1 substrate, indicating that HERC1 negatively regulates ERK signaling by controlling C-RAF stability (43). Similarly, HERC2 ubiquitinates C-RAF to regulate its protein levels and mediates cellular oxidative stress responses, thereby influencing antioxidant gene expression through modulation of the C-RAF/MKK3/P38 signaling axis. Clinically, HERC1/2 expression levels positively correlate with survival rates in RCC patients (44), underscoring their prognostic value. Notably, although HERC1 and HERC2 share C-RAF as a common substrate, they predominantly govern proliferative and stress signaling pathways, respectively; the mechanistic basis for their spatiotemporal functional divergence warrants further investigation.

FBXW7 is frequently inactivated in RCC through mechanisms encompassing genetic alterations, transcriptional repression, and aberrant protein stability/complex assembly. Specifically: the FBXW7 gene can be disrupted by chromosomal translocation t(3;4)(q21;q31) in certain RCC cases, with concomitant loss of the derivative chromosome resulting in functional deletion (45); approximately 4% of Wilms tumors harbor FBXW7 mutations or deletions, and 8.7% (9/104) of cases exhibit amplification of MYCN—MLST8 (mTOR substrate for FBXW7, MLST8-mediated ubiquitination and degradation) (46); Functional miRNAs such as miR-92a-3p are significantly overexpressed in RCC, inhibiting FBXW7 translation by targeting its 3’ UTR and serving as key upstream regulators driving FBXW7 downregulation (47). Clinical sample analyses reveal that FBXW7 expression in RCC tissues is significantly lower than in adjacent normal tissues and negatively correlates with pathological grade and TNM stage (48). Functionally, FBXW7 serves as the substrate recognition component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, exerting tumor-suppressive activity through K48-linked polyubiquitination and proteasomal degradation of oncogenic drivers such as cyclin E, c-Myc, c-Jun, Notch-1, and AURKA (49); notably, deletion of its F-box domain abrogates assembly of the functional SCF complex (50) Collectively, FBXW7 inactivation drives RCC progression through multi-level mechanisms initiated by genetic alterations, accelerated transcriptional silencing by miRNAs, decreased protein stability, and functional complex disassembly. Specifically, FBXW7 inactivation precipitates dysregulation of three major oncogenic axes. For instance, FBXW7 inactivation promotes clear cell RCC (ccRCC) progression through MLST8(MTOR-associated protein,MLST8 homolog)-driven oncogenic signaling. Mechanistically, CDK1 phosphorylates FBXW7 to enable recognition of the (T/S)PXX(S/T/D/E) degron motif in MLST8 and subsequent K48-linked ubiquitination and degradation. FBXW7 loss or CDK1 overexpression leads to MLST8 accumulation, mTOR pathway activation, and enhanced cell proliferation and migration. In vitro studies confirm that this axis serves as a critical mediator of FBXW7 inactivation-induced tumorigenesis (51).

FBXW7 orchestrates a positive feedback loop with its substrates NFAT1 (Nuclear Factor of Activated T Cells 1) and PRR11 (Proline-rich Protein 11) to drive ccRCC progression. NFAT1, an FBXW7 substrate involved in tumor immunity, is aberrantly overexpressed in ccRCC and associated with poor prognosis. It is stabilized via hyperactivation of the PI3K/AKT/GSK-3β axis, leading to PD-L1 upregulation, immune escape, and resistance to sunitinib. Moreover, FOXA1/SETD2 downregulation causes FBXW7 loss, allowing NFAT1 to evade FBXW7-mediated K48 ubiquitination and degradation, thereby establishing a positive feedback circuit (52). PRR11 represents another FBXW7 substrate that undergoes GSK3β phosphorylation followed by FBXW7-catalyzed K48 ubiquitination and degradation. However, PRR11 concurrently activates AKT, which inhibits GSK3β activity, enabling PRR11 to escape degradation, block DNA oxidative damage, and accelerate RCC progression (53).

The FBXW7 substrate repertoire in renal cancer exhibits a “functional trifurcation” pattern: MLST8, NFAT1, and PRR11 correspond to three core events—metabolic reprogramming, immune evasion, and genomic stability—establishing FBXW7 as a molecular hub. Current studies are limited to single-substrate validation; construction of a co-degradation atlas to delineate pathway crosstalk and assessment of therapeutic windows and toxicities for combinatorial interventions are urgently needed. In RCC, FBXW7 inactivation results from the synergistic cooperation of genetic events and aberrant signaling pathways, wherein functional sequestration of FBXW7 due to AKT-mediated GSK3β inactivation is an important RCC-specific mechanism that provides a novel conceptual framework for for targeted therapy.

MDM2 (491 amino acids) exerts E3 ligase activity via its C-terminal RING finger domain to catalyze p53 ubiquitination and degradation, thereby antagonizing p53’s tumor-suppressive function (54). MDM2 dysregulation in kidney cancer stems from multi-layered regulatory abnormalities, with its overexpression driven by the combined effects of gene amplification, transcriptional activation, and pathway crosstalk. For instance, in a subset of ccRCC, amplification of the 12q14–15 chromosomal region where MDM2 resides directly increases gene copy number (55). Furthermore, sustained activation of the p53-MDM2 negative feedback loop also contributes to this process (56). These abnormalities collectively lead to MDM2 overexpression; clinical data demonstrate that, in clear cell RCC (ccRCC), MDM2 positivity reaches 54.5%, and MDM2/p53 co-expression correlates with shortened overall survival (OS) (57), suggesting that targeting the MDM2-p53 axis represents a strategy for restoring p53 function and inhibiting RCC progression.

TRIMs (Tripartite Motif) proteins represent a family of RING finger domain-containing E3 ubiquitin ligases. Certain members exhibit aberrant expression in malignancies, driving tumorigenesis and progression by orchestrating dysregulated signaling pathways through substrate ubiquitination (58). In recent years, an increasing number of studies have shown that members of the TRIM members are also involved in the regulation of RCC. Specifically, TRIM21, TRIM44, TRIM65 and TRIM47 have emerged as key regulatory factors in this area, which is attributed to their well-elucidated mechanisms and clinical relevance in tumor initiation and progression.

TRIM21 as a multifunctional tumor suppressor. Studies have revealed that TRIM21 is downregulated in primary ccRCC and predicts poor prognosis. TRIM21 suppresses tumor cell glycolysis, proliferation, tumorigenesis, migration, and metastasis by ubiquitinating and degrading HIF-1α (59). Additionally, TRIM21 negatively regulates lipogenesis by mediating K48-linked ubiquitination and degradation of SREBF1 (Sterol Regulatory Element-Binding Transcription Factor 1), which downregulates fatty acid synthase and reduces intracellular lipid content (60). Regarding tumor microenvironment regulation, AXL (AXL Receptor Tyrosine Kinase) is an independent prognostic indicator of poor outcome in KIRC; its stability is subject to competing regulation by TRIM21 and the deubiquitinase STAMBPL1 (STAM Binding Protein-Like 1). TRIM21 promotes AXL degradation via K48-linked ubiquitination, thereby suppressing EMT and stem cell phenotypes, while enhancing CD8⁺ T cell function to improve immunotherapy sensitivity (61). ASS1 (Argininosuccinate Synthetase 1), a key enzyme in the urea cycle whose aberrant expression is linked to tumor progression in multiple cancers (62), is stabilized by TRIM21 through K63-linked ubiquitination, leading to suppression of the mTORC1-EMT axis and inhibition of ccRCC cell invasion and migration (63). This metabolic–metastatic pathway represents a recent discovery, and functional characterization remains limited to ccRCC models. Collectively, TRIM21 integrates hypoxia metabolism, lipogenesis, receptor signaling, and the immune microenvironment, constituting a reversible tumor-suppressive hub in ccRCC.

TRIM44 also as a tumor suppressor; TRIM44 functions as an E3 ubiquitin ligase in RCC (64). TRIM44 is upregulated in RCC tissues and mediates FRK (Fyn-Related Kinase) ubiquitination and degradation (65). TRIM44 also degrades the EMT core marker vimentin via K48-linked ubiquitination, thereby inhibiting RCC invasion and migration (66).

Furthermore, TRIM47 and TRIM65 have been identified as oncogenic factors in RCC, both of which are highly expressed and associated with shortened overall survival. TRIM47 drives tumor progression by enhancing its E3 ubiquitin ligase activity to promote p53 ubiquitination and degradation, thereby abrogating p53’s tumor-suppressive function (67); TRIM65 catalyzes K48-linked ubiquitination and degradation of BTG3 (BTG anti-proliferation factor 3) at lysine 41, alleviating G2/M phase arrest and promoting proliferation. Clinical tissue microarray analysis reveals that TRIM65 expression negatively correlates with BTG3 levels (68).

In summary, TRIM family E3 ubiquitin ligases display a bidirectional regulatory pattern in RCC, with certain members downregulated (e.g., TRIM21) and others upregulated (TRIM44, TRIM47, TRIM65), and their expression levels are significantly correlated with prognosis. Among them, TRIM21 exhibits the most pleiotropic functions, acting as a critical tumor suppressor hub by orchestrating hypoxic metabolism, lipid synthesis, receptor signaling, and the immune microenvironment through mechanisms including ubiquitin-mediated degradation of HIF-1α, SREBF1, and AXL, as well as stabilization of ASS1. TRIM47 and TRIM65 exert oncogenic roles through degrading p53 and BTG3, respectively. Collectively, TRIM proteins regulate multiple substrates to participate in fundamental processes of ccRCC, including proliferation, metabolism, EMT, and immune evasion. Their expression profiles and functional heterogeneity provide potential biomarkers for prognostic assessment and therapeutic windows for targeted intervention.

Nevertheless, limitations persist. Notably, the upstream mechanisms—such as gene amplification, transcriptional activation, and signaling pathway regulation—underlying the upregulated expression or enhanced activity of certain TRIM proteins in RCC remain poorly defined. This constitutes a critical knowledge gap in the field and a limitation that must be explicitly acknowledged.

VHL (Von Hippel-Lindau) belongs to the Cullin-2 family of E3 ubiquitin ligases. In ccRCC, the VHL protein functions as the substrate recognition subunit of the Cullin-2 RING-E3 ligase complex, coordinating with elongin B/C, Cullin-2, and Rbx1 to mediate substrate ubiquitination and proteasomal degradation (69, 70). Specifically, hypoxia and oxygen-sensing mechanisms in ccRCC center on the “VHL-PHD-HIF” axis, accompanied by multiple bypass pathways and metabolic reprogramming. Under normoxic conditions, PHD1/2/3 hydroxylate HIF-α at Pro402/564 in the presence of O₂, Fe²⁺, and 2-oxoglutarate, then CRL2VHL recognizes this hydroxylated degron and mediates K48-linked ubiquitin chain assembly, targeting HIF-α for rapid degradation by the 26S proteasome; conversely, under hypoxia or in the presence of Fe²⁺/CoCl₂ mimetics, hydroxylation is impeded, allowing HIF-α to escape degradation and activate downstream oncogenic transcriptional programs (71–75) (Figure 2). Notably, loss of the short arm of chromosome 3 (3p) occurs in over 90% of sporadic ccRCC, leading to single-copy loss of the VHL gene. This 3p deletion concurrently causes haploinsufficiency of adjacent tumor suppressor genes (PBRM1, BAP1, SETD2), forming a cooperative oncogenic network with VHL (76). Aberrant hypermethylation of the CpG island in the 5’ region of the VHL gene directly inhibits gene transcription, resulting in loss of protein expression and producing effects equivalent to a gene mutation (77). Approximately 20% of cases achieve biallelic inactivation of VHL through promoter methylation without accompanying gene sequence alterations (78). In summary, VHL inactivation can be achieved through genetic (point mutations, deletions) and/or epigenetic (promoter methylation) mechanisms, constituting the earliest driver event. VHL targets hydroxylated HIF-1/2α for ubiquitination and degradation. Inactivating mutations in VHL can lead to the accumulation of HIF-1/2α, thereby causing the HIF signaling pathway to be abnormally activated (79). Moreover, HIF-1α predominantly drives angiogenesis and proliferation, whereas HIF-2α promotes invasion and inflammatory responses (80). Beyond the aforementioned classical substrates, CRL2VHL catalyzes the ubiquitin-proteasomal degradation of additional substrates, including ZHX2, SFMBT1, NDRG3, UBE3B, and AURKA. Specifically, ZHX2 undergoes hydroxylation at Pro427/440/464 and is subsequently recognized by VHL, thereby facilitating ccRCC progression through regulating NF-κB/p65 nuclear localization (81–84). At the metabolic level, studies have shown that in ccRCC, the high expression of HIF-1α mediated by VHL inactivating mutations promotes lipid synthesis by upregulating ACLY (acetyl-CoA carboxylase), thereby facilitating tumor progression (85). Additionally, it has been found that the absence of VHL in sporadic ccRCC specimens is associated with a significant increase in autophagy levels, and this elevated autophagy is related to poor patient prognosis. In the autophagy axis, further research has revealed that VHL inhibits autophagy through a PHD1-dependent hydroxylation mechanism of Beclin1, thereby suppressing tumor growth; this indicates that the loss of VHL not only promotes autophagy but is also associated with tumor growth and poor prognosis. Conversely, VHL deficiency leads to hyperactivation of autophagy, which correlates with poor prognosis (86). Moreover, at the epitranscriptomic level, studies have found that VHL regulates the formation of the METTL3/METTL14 complex (the main components of the m6A methyltransferase complex), thereby affecting the stability and protein levels of PIK3R3 mRNA, and consequently modulating the PI3K/AKT signaling pathway, which ultimately impacts the occurrence of renal tumorigenesis (87). Meanwhile, the function of VHL in renal cancer is also closely related to the immune microenvironment. Specifically, VHL mutations reduce naive CD4⁺ T cell infiltration and increase the proportion of memory CD4⁺ T cells (88). Moreover, VHL regulates the expression of VCAM-1 in an NF-κB-dependent manner, thereby promoting the immune response against RCC (89). In summary, the mechanisms of action of VHL in ccRCC are complex and diverse, involving multiple aspects, including the HIF, PI3K/AKT, and lipid metabolism pathways, and the immune microenvironment. Further research into the functions and related mechanisms of VHL will provide new ideas and strategies for the precise diagnosis and treatment of ccRCC.

Illustration of the cellular response to oxygen levels, showing the pathways of HIF-1a and HIF-2a under normoxia and hypoxia. Under normoxia, prolyl hydroxylation leads to VHL-mediated degradation of HIF proteins. Hypoxia inhibits prolyl hydroxylation, stabilizing HIFs, which translocate to the nucleus to form complexes with ARNT, affecting gene expression.

Some USPs act as carcinogenic factors, such as USP7, which is one of the most functionally versatile oncogenic DUBs. USP7 promotes RCC cell proliferation and G1/S phase progression by deubiquitinating and stabilizing ARMC5 (Armadillo Repeat Containing 5) (99). Intriguingly, USP7 overexpression in RCC predicts poor prognosis. USP7 inhibition blocks tumor progression in vitro and in vivo, as FUBP1/3 transcriptionally activates USP7 to subsequently stabilize HIF-2α, forming an oncogenic axis. Afatinib synergistically induces cell death by inhibiting FUBPs and augmenting USP7 downregulation-mediated HIF-2α degradation (100). USP13, identified as a ZHX2 deubiquitinase through DUB cDNA library screening, stabilizes ZHX2 protein via deubiquitination and modulates the ZHX2-NF-κB target gene signature. Knockdown of USP13 significantly inhibits ccRCC colony formation and anchorage-independent growth (101).

USP35 is another important oncogene. USP35 is highly expressed and independently predicts poor survival. It deubiquitinates the IAP family and NRF2 to suppress apoptosis and ferroptosis; knockdown downregulates NRF2 antioxidant target genes and enhances ferroptosis sensitivity. Additionally, USP35 silencing significantly reduces ccRCC xenograft tumor formation (102). Metabolomic analyses further reveal that high USP35 expression activates glycerophospholipid/linoleic acid oncogenic pathways, whereas its downregulation shifts metabolism toward nitrogen/purine metabolism and enhances immunogenicity (103), revealing its novel function in metabolic reprogramming.

Although the substrates of USP39 associated with its canonical DUB activity remain elusive, studies have demonstrated that knockdown of USP39 significantly inhibits AKT phosphorylation at Ser473, blocks AKT signaling activation, and thereby suppresses RCC metastasis and migration (104). In addition, USP39 was found to be highly expressed in RCC and associated with poor survival. USP39 binds SRPK1 (Serine/arginine-rich splicing factor kinase 1) through its 101–565 fragment, promoting SRPK1-SRSF1 (Serine and arginine-rich splicing factor 1) phosphorylation and interaction, which subsequently regulates VEGF-A165b alternative splicing to drive RCC proliferation and angiogenesis (105). Additionally, USP22 is co-upregulated with survivin (an apoptosis inhibitor) in RCC and correlates with poor prognosis; it deubiquitinates and stabilizes survivin, blocks apoptosis, and drives proliferation (106). USP37 binds to HIF-2α and promotes its deubiquitination. Functionally, USP37 knockdown leads to HIF-2α downregulation, inhibition of MTS/2D/3D proliferation, and a significant reduction in orthotopic renal tumorigenesis and spontaneous lung metastasis (107).

Some USPs function as tumor suppressor; for example, USP10 is significantly downregulated in ccRCC, leading to p53 destabilization and loss of growth suppression. Mechanistically, it catalyzes p53 deubiquitination, antagonizes MDM2, and promotes p53 nuclear re-entry. Upon DNA damage, ATM phosphorylates USP10, promoting its nuclear translocation and enhancing p53 stability (108). USP44 is downregulated in ccRCC and correlates with advanced stage, high grade, and poor prognosis. It suppresses proliferation and migration by deubiquitinating and stabilizing p21, degrading Cyclin D1, and negatively regulating JNK phosphorylation (109). USP53 is downregulated in ccRCC and correlates with tumor stage and poor prognosis; its downregulation promotes cell proliferation in vitro and in vivo. Additionally, high levels of USP53 increase the expression of IκB (Inhibitor of κB) and demonstrated that USP53 inhibits the activation of the NF-κB (Nuclear Factor kappa B) pathway by reducing the ubiquitination of IκB, thereby suppressing the proliferation and metastasis of ccRCC cells (110).

Collectively, in ccRCC/RCC, USP7, USP35, USP39, USP22, and USP37 are highly expressed, driving proliferation, ferroptosis evasion, and metabolic reprogramming by stabilizing NRF2, HIF-2α, AKT, and survivin. Validated inhibitors or knockdown rapidly suppress tumor growth. In contrast, USP10, USP44 and USP53 are generally downregulated, resulting in loss of deubiquitinase-mediated restraint on key pathways including NF-κB, JNK and p53. Re-expression or downstream pathway inhibitors can restore tumor-suppressive functions. Differential expression independently predicts poor prognosis. Future studies should elucidate specific molecular mechanisms, such as dissecting FUBPs-USP7 transcriptional regulatory details to optimize inhibitor design. However, USP13 has only been reported once as a ZHX2 stabilizer, and its substrate repertoire and chain topology (K48/K63) remain unexpanded. USP39 also exhibits dual functions in AKT signaling and VEGF splicing, requiring validation of which serves as the primary oncogenic driver.

In addition to the USP family, members of the OTU family play pivotal roles in RCC by regulating core biological processes such as tumor signaling, immune response, and cell death, thereby influencing disease progression.

Members of the OTU family exert diverse regulatory functions in RCC by stabilizing specific substrates. Among them, OTUD1 has been confirmed as an important tumor suppressor. OTUD1 is downregulated in RCC and predicts poor prognosis, exerting tumor-suppressive functions by deubiquitinating and stabilizing PTEN (Phosphatase and Tensin homolog) to regulate the PI3K/AKT and TNF-α/NF-κB signaling pathways (111). Another study revealed that OTUD1 also deubiquitinates and stabilizes STAT3 (Signal Transducer and Activator of Transcription), blocking its nuclear translocation and PD-L1 transcription to enhance anti-tumor immunity (112). This forms a unique anti-cancer immune microenvironment.

In contrast, OTUB1 acts as a clear oncogene. OTUB1 is upregulated in RCC and correlates with poor prognosis. Further studies reveal that OTUB1 stabilizes FOXM1 (Forkhead box protein M1) through deubiquitination, upregulates epithelial cell transforming sequence 2 (ECT2) to activate Rho signaling, and promotes proliferation and migration in vitro; FOXM1 re-expression rescues these phenotypes (113). Additionally, OTUB1 is highly expressed in RCC and positively correlates with PD-L1 abundance; it blocks ERAD-mediated degradation of PD-L1 by deubiquitinating K48-linked chains, thereby enhancing PD-1 binding and suppressing CD8⁺ T cell infiltration and IFN-γ secretion (114).

In terms of metabolism and stress regulation, OTUD3 is highly expressed in ccRCC and promotes cell proliferation, suppresses ferroptosis, and affects cellular reactive oxygen species (ROS) levels by deubiquitinating and stabilizing SLC7A11 (Solute carrier family 7 member 11) (115). In RCC tissues, both OTUD6A and CDC6 (Cell Division Cycle 6) protein levels are elevated. OTUD6A promotes tumor proliferation and chemoresistance by deubiquitinating CDC6 and cleaving K6/K33/K48-linked ubiquitin chains, thereby antagonizing proteasomal degradation, activating the ATR-Chk1 signaling pathway, and enhancing DNA repair (116). OTUD6B is also an oncogene (117). In ccRCC patients with VHL missense mutations, low OTUD6B expression predicts shorter overall survival. OTUD6B knockdown enhances ccRCC cell migration and HIF-2α levels in a mutant VHL protein-dependent manner, whereas OTUD6B overexpression reverses these phenotypes (118).

BAP1 (BRCA1-associated protein 1) belongs to the UCH subfamily of deubiquitinating enzymes (DUBs) (119). BAP1 is a key inactivated gene in RCC (120), whose inactivation is primarily achieved through a “two-hit” model involving chromosome 3p deletion and gene mutation. This process synergizes with VHL inactivation to drive the development and progression of high-grade, metabolically reprogrammed, and immune-infiltrated ccRCC. Following BAP1 inactivation, its diverse functions as a deubiquitinase are compromised (76). Studies have identified BAP1 inactivation in RCC and demonstrated its association with poor prognosis. It suppresses proliferation by binding HCF-1 (Host Cell Factor-1) to recruit chromatin-remodeling complexes; loss of this function leads to cell cycle dysregulation (121). Another member, UCHL5, plays a cancer-promoting role. UCHL5 is highly expressed in the UCH family and correlates with poor prognosis. It drives EMT and metastasis by deubiquitinating and stabilizing Snail1 (Snail family transcriptional repressor 1), and is associated with impaired antigen presentation by tumor-infiltrating B cells (122).

OTU/UCH deubiquitinases exert dual roles in RCC. Tumor-suppressive members (OTUD1, BAP1) inhibit tumor growth and enhance immunity by stabilizing substrates such as PTEN, STAT3, among others. Oncogenic members (OTUB1, OTUD6A/6B, OTUD3, UCHL5) activate proliferation, immune evasion, DNA repair, and EMT pathways by stabilizing substrates, including FOXM1, PD-L1, CDC6, SLC7A11, and Snail1, leading to poor prognosis. Differential expression among members collectively forms a deubiquitination regulatory network in RCC (Table 2).

The roles of these E3 ligases and deubiquitinases in RCC are summarized in Table 2, and the core signaling pathways they are involved in are shown in (Figure 3).