The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma

Abstract

Ubiquitination, a key post-translational modification, is responsible for regulating protein stability, activity, subcellular localization, and interactions via the ubiquitin–proteasome system (UPS). The UPS plays a role in non-lysosomal protein degradation, involved in the coordinated action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). The review elaborates on the functions of key E3 ligases of MDM2, β-TrCP, and SCF complexes, which modulate cell cycle progression, apoptosis, metabolic reprogramming, and drug resistance in hepatocellular carcinoma (HCC). For instance, MDM2 promotes HCC development by degrading the tumor suppressor p53, while β-TrCP influences the Wnt/β-catenin signaling axis by changing β-catenin levels. Deubiquitinating enzymes (DUBs), including the USP family and CYLD, also play significant roles in HCC by stabilizing or destabilizing critical proteins involved in oncogenesis. The clinical potential of ubiquitination-related molecules as biomarkers for predicting HCC prognosis and as therapeutic targets is also discussed. This review comprehensively examines the role of ubiquitination modification in HCC and its clinical relevance. Future research directions include the exploration of novel ubiquitination modifications, their interactions with other post-translational modifications, and the development of precision medicine strategies based on multi-omics technologies to improve HCC treatment outcomes.

Graphical Abstract

Introduction

Biological significance of ubiquitination modification

In human cells, there exist two key protein degradation pathways: the ubiquitin–proteasome system (UPS) and lysosomal autophagy pathway (Fig. 1A). The traditional view holds the view of UPS’s dominant role in intracellular protein degradation, while in stressful conditions of nutrient deficiency and hypoxia, lysosomal autophagy is significantly enhanced for protein and organelle renewal. In hepatocellular carcinoma, lysosomal autophagy can participate in the metabolic reprogramming and malignant progression regulation of tumor cells by selectively degrading specific proteins HK2(Jiao et al. 2018). The roles of the UPS and lysosomal autophagy in hepatocellular carcinoma are not isolated but interrelated through complex network regulatory mechanisms, jointly influencing the occurrence and development of tumors.

Fig. 1.

Two molecular mechanisms and interrelationships of major protein degradation pathways of autophagy (A) and the UPS (B)

Ubiquitination remains an essential post-translational bioprocess within cells, managing protein stability, activity, subcellular localization, and interactions by covalently conjugating ubiquitin molecules to target proteins. It is extensively involved in physiological bioprocesses such as cell proliferation, apoptosis, autophagy, DNA damage repair, and immune responses, maintaining intracellular protein homeostasis(Çetin et al. 2021). The process of covalently conjugating one or more ubiquitin molecules to substrate proteins based on several enzymatic reactions is termed ubiquitination modification. The ubiquitination modification of proteins is primarily regulated by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), encompassing three enzymatic reaction processes: ① E1 activates ubiquitin in an ATP-dependent manner; ② E1 transfers ubiquitin to the cysteine residue of E2 after binding with E2; ③ The ubiquitin bound to E2 is transferred to specific substrates by E3, ubiquitinating the substrates (Fig. 1B).

Composition and function of the UPS

The UPS serves as the chief mechanism for non-lysosomal protein breakdown in cells, handling the most proteins in eukaryotes. It primarily consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), deubiquitinating enzymes (DUBs), and 26S proteasomes (Rousseau and Bertolotti 2018; Thibaudeau and Smith 2019). Considering the specific structural domains that are engaged in the ubiquitin transfer to target proteins, E3s are further classified into three categories: HECT-domain-containing E3s, RING-domain-containing E3s, and U-box-domain-containing E3s. HECT-domain-containing E3s include NEDD4, which is involved in regulating membrane protein transport and degradation. RING E3s acts as a scaffold protein, directly catalyzing ubiquitin transfer without forming an E3-ubiquitin intermediate. They include SCF(SKP1-CUL1-F-box), MDM2, FBXW7, and so on. The structure of U-box E3s is similar to that of RING, but it lacks a complete zinc binding site such as PARKIN. The UPS marks proteins for ubiquitination, enabling their recognition and degradation by proteasomes, thereby regulating protein turnover and homeostasis within cells(Kleiger and Mayor 2014).

The DUB family consists of proteases that hydrolyze ester, peptide, or isopeptide bonds at ubiquitin's carboxyl terminus, and they are tasked with the specific removal of ubiquitin from ubiquitinated proteins or precursor proteins(Snyder and Silva 2021). Protein ubiquitination is achieved through a cascade reaction of the E1-E2-E3 enzyme system, in which the E3 ligase specifically recognizes the substrate and catalyzes the formation of ubiquitin chains. Reverse regulation, on the other hand, is independently accomplished by DUBs, which remove ubiquitin markers by hydrolyzing the ubiquiquin-substrate isopeptide bonds, thereby maintaining the dynamic balance of protein homeostasis(Song et al. 2025). Recent investigations found that USP7 maintained the stability of DDX5 by eliminating ubiquitin chains through deubiquitination to further upregulate the fatty acid synthesis and support the HCC progression (Wang et al. 2025a). Another study indicated the upregulation of USP8 activated Wnt/β-catenin axis through the post-translational mechanism of β -catenin to facilitate the advancement of HCC and inhibit ferroptosis (Tang et al. 2023a). Research on the treatment of DUB is currently in the preclinical or early clinical stage, while its multi-pathway regulatory characteristics make it a promising direction for precise treatment of HCC, especially for advanced HCC patients. Future research needs to further clarify the differences in the role of DUB among various HCC subtypes and develop more selective DUB inhibitors to achieve more precise targeted therapy.

Types of ubiquitination and their regulatory mechanisms

Monoubiquitination and polyubiquitination are the two forms of ubiquitination (Fig. 2A). As a post-translational modification (PTM), monoubiquitination refers to the process in which one ubiquitin molecule is covalently bound to a lysine residue of a substrate protein (Chen et al. 2022a). Monoubiquitination usually fail to regulate protein degradation, whereas regulate the subcellular localization, protein–protein interactions, or endocytosis of the substrate. Polyubiquitination was named as the ubiquitin modified at a certain site of the substrate protein with chain extension, forming homologous or heterologous ubiquitin chains(Gandu et al. 2025). During polyubiquitination, ubiquitin molecules can form different types of ubiquitin chains through their lysine residues such as K48 and K63 and the N-terminal methionine residue (M1) (Fig. 2B). K48-linked polyubiquitination primarily mediates proteasome degradation, while K63-linked polyubiquitination is involved in DNA repair and endocytosis (Pellegrino et al. 2022; Min et al. 2023; Guo et al. 2025). Emerging evidence indicates that branched K11/K48-linked polyubiquitin chains actively promote proteasomal degradation during mitosis (Boughton et al. 2020). As a circular finger type E3 ligase, Nrdp1 terminates the early TCR signaling in CD8⁺ T cells by mediating the Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoting the dephosphorylation of Zap70 by acid phosphatase-like proteins Sts1 and Sts2 (Yang et al. 2015). The lysine 27 residue of ubiquitin (K27) is not only essential for RNF168-dependent chromatin ubiquitination but also constitutes the predominant ubiquitin-based modification on chromatin following DNA damage (Gatti et al. 2015). In addition, the synthesis of M1-linked ubiquitin chains by LUBAC facilitates STING-induced innate immune such as NF-κB and IRF3 signaling axis (Fischer et al. 2025).

Fig. 2.

A Classification of ubiquitin: monoubiquitination and polyubiquitination. B Different biological functions of polyubiquitination mediated by it through different junction sites such as K48, K63, K11, K6, K27, K33, and M1, which were labeled beside the ubiquitin chains

Current status and challenges of hepatocellular carcinoma (HCC)

Epidemiology and clinical treatment challenges of HCC

Hepatocellular carcinoma (HCC), a primary liver malignancy originating from hepatocytes, constitutes the overwhelming majority of primary liver cancer cases (Chakraborty and Sarkar 2022). The global incidence of liver cancer is on the rise, which is estimated that the number of new cases will increase to 1.52 million by 2050, a 76% increase compared to 2022(Chan et al. 2025; Bray et al. 2024). The incidence rates of HCC vary significantly across regions and shows an upward trend in some areas. It is a high-incidence area in Southeast Asia, the Western Pacific and Southeastern Africa (Siegel et al. 2024). The challenges in HCC treatment lie in its inconspicuous early symptoms, with most patients diagnosed at an advanced stage and insensitive to chemotherapy and radiotherapy. Immune checkpoint inhibitor (ICI)-based therapies have emerged as innovative treatment modalities for advanced hepatocellular carcinoma (HCC). However, only one-third of patients exhibit an objective response to these therapies, primarily due to the progression of primary or acquired resistance (Sonkin et al. 2024). Additionally, HCC has a high recurrence rate, and postoperative recurrence and metastasis are the primary factors affecting patient survival (Rousseau and Bertolotti 2018).

Crucial role of abnormal protein modifications in the occurrence and development of HCC

Abnormal protein modifications function in the genesis and development of HCC. For instance, ubiquitination dysregulation can lead to intracellular protein homeostasis imbalance, further affecting cell cycle regulation, DNA damage repair, and other processes, promoting HCC development (Min et al. 2023; Chen et al. 2025). Furthermore, abnormal phosphorylation and acetylation modifications are also closely related to HCC progression. These abnormal modifications may promote tumor cell proliferation, invasion, and metastasis by affecting the activation or inhibition of signaling pathways (Rousseau and Bertolotti 2018; Min et al. 2023).

Increasing evidence has underscored ubiquitination—a complex post-translational modification system—as a pivotal regulator of immune homeostasis in the pathogenesis of HCC (Zhao et al. 2025). Ubiquitination plays multifaceted and crucial roles in the occurrence and development of HCC, involving protein degradation, signal transduction, cell cycle regulation, and apoptosis. For example, ubiquitination of the p62 protein is essential in HCC. TRIM21 regulates the p62-Keap1-Nrf2 pathway through its E3 ubiquitin ligase activity, promoting HCC development. Under protein toxic stress and oxidative stress induction, TRIM21 ubiquitinates p62 at lysine K7 through K63 linkage, hindering p62 oligomerization and binding to Keap1, inhibiting the p62-Keap1-Nrf2 antioxidant stress pathway, increasing cellular oxidative damage, and inducing HCC (Feng et al. 2021). Additionally, NEDD4, as a ubiquitin ligase, promotes tumor growth and metastasis in HCC by inhibiting the expression and activity of PTEN (Wan et al. 2021). NAP1L1 affects the progression of HCC cells by regulating ubiquitination of BIRC2 (Zhang et al. 2024a). OTUB1 stabilizes RACK1 through non-canonical ubiquitination, which regulates the occurrence and development of HCC (Peng et al. 2024). These ubiquitination processes jointly promote the occurrence and development of HCC by regulating the stability, activity, and signal transduction of key proteins.

In HCC, ubiquitination and SUMOylation modifications are also part of cellular metabolism regulation. For instance, FBXO7 promotes PRMT1 degradation through ubiquitination, thereby weakening PHGDH arginine methylation and activation, leading to impaired serine synthesis, reactive oxygen species (ROS) accumulation, and ultimately inhibiting HCC cell growth (Zhu et al. 2022). Furthermore, USP27X-AS1 promotes HCC progression by recruiting USP7 to deubiquitinate AKT. These findings support that ubiquitination plays a complex and critical role in HCC metabolic regulation and signal transduction, providing potential targets for HCC treatment (Su et al. 2024).

Through many studies have identified the role of abnormal ubiquitination in hepatocellular carcinoma pathology (Zhang et al. 2024b; Wang et al. 2024a; Zhao et al. 2022), this review aims to further gather the mechanisms of ubiquitination regulation in HCC and provides more evidence of ubiquitination-related therapies for HCC.

Core mechanisms of ubiquitination regulation in HCC

Key E3 ligases and HCC

MDM2/p53 pathway (regulating cell cycle and apoptosis)

MDM2, an E3 ubiquitin ligase, primarily mediates the stability of p53 through ubiquitination (Koo et al. 2022). In HCC, MDM2 overexpression or increased activity may lead to increased p53 degradation, thereby inhibiting its function. PTEN stability is regulated by NEDD4-mediated ubiquitination and degradation (Ding et al. 2023; Meng et al. 2014). Upregulation of NEDD4 expression may lead to increased PTEN degradation, promoting tumorigenesis. p53, a pivotal tumor suppressor protein, governs cell cycle progression, DNA repair, and apoptosis (Ke et al. 2022). MDM2 modulates p53 function through multiple mechanisms, including direct binding and inhibition of p53 transcriptional activity (Pellot Ortiz et al. 2023), promotion of p53 ubiquitination and proteasomal degradation (Wasylishen and Lozano 2016), enhancement of p21Waf1 degradation via conformational changes (Xu et al. 2010), augmentation of its E3 activity through SUMOylation interactions (Nie et al. 2010), and formation of an autoregulatory feedback loop with p53 (Pellot Ortiz et al. 2023). In tumors, MDM2 overexpression is closely associated with poor prognosis, as its amplification leads to excessive p53 degradation and decreased activity, thereby promoting tumorigenesis and progression (Pellot Ortiz et al. 2023). Additionally, MDM2 affects p53 function through other pathways, such as ATM-mediated β-TRCP-dependent ubiquitination and degradation of MDM2 under DNA damage stress, which impacts p53 stability (Wang et al. 2012). MDM2 inhibitors stabilize p53 by binding to its N-terminal domain and inhibiting MDM2-mediated p53 degradation (Zhao et al. 2021). By adding ubiquitin chains to specific lysine residues of p53, MDM2 promotes p53 degradation, thus inhibiting its function. Furthermore, deubiquitinating enzymes such as USP10 and USP42 stabilize p53 protein by removing ubiquitin chains from p53 (Yuan et al. 2010; Hock et al. 2011), thereby inhibiting tumorigenesis. USP7 is involved in the treatment and immune aspects of HCC. However, in some cases, USP7 may promote tumor progression by stabilizing other oncoproteins (Dai et al. 2020; Tang et al. 2024). Other study reveals that FEN1 inactivates p53 signaling by recruiting USP7, which stabilizes mouse double minute 2 (MDM2) by preventing its ubiquitination and degradation (Bian et al. 2022). ER stress in cancer cells is caused by the accumulation of polyubiquitinated proteins, which occurs when USP7 inhibitors suppress deubiquitinating enzyme activities (Lee et al. 2016). In tumors with wild type p53 (Wt-p53), the inhibition of USP7 triggers the breakdown of MDM2/MDMX, activating p53 signaling and causing cell cycle arrest and apoptosis (Saha and Ghosh 2025).

β-TrCP (Wnt/β-catenin signaling regulation)

β-TrCP, identified as an E3 ubiquitin ligase(Simonetta et al. 2019), contributes to the regulation of the Wnt/β-catenin signaling axis(Azzolin et al. 2014). Under normal conditions, β-catenin is maintained at low levels through β-TrCP-mediated ubiquitination and degradation. Upon Wnt signal activation, β-catenin degradation is inhibited, leading to its accumulation within the cell and translocation to the nucleus, where it triggers the expression of downstream genes and boosts cell proliferation (Zhang and Wang 2020; Sarode et al. 2020). In HCC, abnormal expression or altered activity of β-TrCP may result in abnormal accumulation of β-catenin, thereby activating the Wnt/β-catenin signaling pathway and promoting tumorigenesis and progression (Xu et al. 2025; Luo et al. 2024a).

Abnormal expression or altered activity of β-TrCP can lead to abnormal accumulation of β-catenin by affecting its phosphorylation, ubiquitination, and degradation pathways. Normally, phosphorylated β-catenin by the Axin and GSK-3β complex enables recognition and binding by β-TrCP (Aberle et al. 1997). As a component of E3 ligase, β-TrCP mediates the polyubiquitination and degradation of β-catenin through the ubiquitin–proteasome system, thereby maintaining a low level of β-catenin in the cytoplasm(Liu et al. 1999). When the expression of β-TrCP is decreased, its function is impaired, or its binding to phosphorylated β-catenin is blocked, it will lead to the obstruction of β-catenin degradation, thereby stably accumulating in the cytoplasm and being transported to the nucleus, activating the transcription of downstream target genes in the Wnt/β-catenin signaling pathway (Liu et al. 1999; Ougolkov et al. 2004). Additionally, abnormal accumulation of β-catenin improves the transcriptional activity, for example, AKT enhances β-catenin's ability to interact with T-cell factor receptors through phosphorylation, while p300 increases β-catenin's affinity for Tcf4 through acetylation, further potentiating its transcriptional activity (Fang et al. 2007; Lévy et al. 2004). This abnormal accumulation and activation occur in various cancers, such as colorectal cancer, and β-TrCP dysfunction can also affect the NF-κB signaling axis, further exacerbating cancer progression (Ougolkov et al. 2004; Winston et al. 1999).

SCF complex

The SCF complex is an E3 ubiquitin ligase complex(Cao et al. 2023), with FBXW7 serving as its critical recognition component (Lan and Sun 2019). The SCF^FBXW5 complex directly ubiquitinates AQP3, resulting in the lysosomal-dependent degradation of PDPK1/PDK1, which in turn inactivates the AKT-MTOR pathway and triggers autophagic death in HCC (Liang et al. 2024). FBXW7 promotes the degradation of various oncoproteins, such as c-Myc, through recognition and ubiquitination (Lan and Sun 2019). In HCC, downregulation of FBXW7 may lead to increased c-Myc stability, thereby promoting cell proliferation and tumor progression (Boretto et al. 2024; Yeh et al. 2018; Motomura et al. 2024). For instance, FBXO7 inhibits PHGDH methylation by ubiquitinating PRMT1, thereby suppressing serine synthesis and cell proliferation (Wang et al. 2023a; Luo et al. 2024b). PRMT9 is an oncogene crucial for HCC invasion and metastasis, influencing EMT by modulating Snail expression via the PI3K/Akt/GSK-3β/Snail signaling axis(Jiang et al. 2018). FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 ubiquitination and subsequent degradation, while targeting the CAND1-SCF^FBXO11-hnRNPA2B1 axis serves as a novel mechanism for HCC (Zhang et al. 2023a).

E3s and metabolic reprogramming

Metabolic reprogramming is the main trait of cancer. Normally, differentiated cells primarily use mitochondrial oxidative phosphorylation for energy, whereas most tumor cells rely on aerobic glycolysis, a process called the 'Warburg effect,' leading to the production of large quantities of lactate (Liu et al. 2022). This metabolic mode not only provides energy for tumor cells but also creates an acidic microenvironment, enhancing tumor cell growth, apoptosis resistance, immune escape, and other characteristics (Yang et al. 2023).

Feng et al. found that phosphofructokinase liver type (PFKL), a key enzyme in glycolysis, may be degraded by the E3s member tumor necrosis factor alpha-induced protein 3 (TNFAIP3), thereby inhibiting HCC glycolysis and revealing a novel mechanism by which TNFAIP3 inhibits PFKL and tumor regulation (Feng et al. 2020). Pyruvate kinase M (PKM), another key enzyme in glycolysis, has two distinct isoforms: pyruvate kinase M1 (PKM1), which is expressed in normal tissues to enhance oxidative phosphorylation, and pyruvate kinase M2 (PKM2), which is ubiquitously expressed in tumor areas and helps aerobic glycolysis in tumor cells (Chen et al. 2020). Zinc finger protein 91 (ZFP91) affects PKM splicing by promoting the ubiquitination and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), leading to increased PKM1 isoform formation and decreased PKM2 isoform formation, ultimately inhibiting cell proliferation and metastasis as well as glucose metabolic reprogramming in HCC (Lee et al. 2016). SREBP1c is a critical transcription factor in lipid metabolism (Saha and Ghosh 2025). PHD finger protein 2 (PHF2), which contains a PHD domain, functions as an E3s for SREBP1c, promoting its ubiquitination and degradation, thereby attenuating lipid metabolism and cell proliferation in HCC and exerting a tumor suppressor role (Jeong et al. 2023). HCC maintains its life activities through abnormal metabolic pathways such as aerobic glycolysis and de novo lipid synthesis, while E3s can inhibit tumorigenesis by ubiquitinating and degrading key enzymes involved in glycolysis and lipid metabolism.

Parkin, an E3 ubiquitin ligase (Kane et al. 2014; Quinn et al. 2020), primarily participates in the regulation of mitochondrial quality control and cellular metabolism. In HCC, abnormal expression or dysfunction of Parkin may lead to mitochondrial dysfunction and metabolic reprogramming, thereby promoting tumorigenesis and progression (Yao et al. 2022; Xiong et al. 2025). For example, Parkin maintains mitochondrial quality and function by promoting the ubiquitination and degradation of mitochondrial proteins, thus facilitating mitochondrial autophagy (Zhou et al. 2023; Pickrell and Youle 2015).

E3s and HCC Drug resistance

Chemotherapy remains a primary treatment option for many HCC patients; however, its efficacy remains suboptimal, primarily due to HCC drug resistance (Tang et al. 2020). This resistance may arise from factors such as large tumor burden, tumor heterogeneity, reduced effective exposure of tumors to chemotherapeutic drugs due to physical barriers, and the immune microenvironment. Ankyrin repeat and SOCS box containing 3 (ASB3), a member of the E3s family, has been found an association with poor clinical outcomes which promote the ubiquitination and degradation of death receptor 5 (DR5) (Huang et al. 2024). In mouse models, knockdown of ASB3 stabilized DR5 expression and improved HCC sensitivity to TRAIL, suggesting the potential of targeting ASB3 to treat HCC and overcome TRAIL resistance (Huang et al. 2024). Additionally, Xia et al. identified a novel E3s, FBXW2, which targets transforming growth factor kinase 1 (TAK1) for ubiquitination and degradation, thereby inhibiting HCC progression and sorafenib resistance (Xia et al. 2021). Enhanced drug resistance leads to suboptimal antitumor efficacy; however, E3s can improve tumor sensitivity to drugs by degrading proteins associated with tumor resistance. These results hold a theoretical basis for the development of potential anti-resistance targets and may significantly enhance antitumor efficacy when combined with antitumor drugs.

Role of DUBs in HCC

Ubiquitination, as a reversible post-translational modification, involves the removal of ubiquitin molecules from substrates, a process catalyzed by DUBs' ubiquitin-specific proteases (Fig. 3). Among Fig. 3, Raf-1 activates MEK and then phosphorylates ERK, regulating downstream target genes to promote the progression of HCC. IKKβ phosphorylates IκBα is degraded by the 26S proteasome, releasing the β65/P50 dimer into the nucleus to regulate HCC-related genes. HBX/SOCS1 complex inhibits the degradation of IκBα, while E3 ligases such as TRIM7 and NEK2 can promote the ubiquitination and degradation of IκBα. HBX/MYH9 complex enhances the nuclear translocation of β-catenin by inhibiting the activity of GSK3, promoting the progression of HCC. TAK1 activates MKK, thereby phosphorylating JNK/P38. HDIBP regulates the ubiquitination degradation of TWist1 through the TAK1-ITCH axis, while JNK activation can promote the progression of HCC. In addition, GSK3, β-catenin, and IKBα are catalyzed by specific E3 ligases such as TRIM7, NEK2, and ITCH, and degraded by the 26S proteasome, directly affecting the progression of HCC.

Fig. 3.

The regulatory network of key molecules in the ubiquitin–proteasome pathway in the progression of HCC

USP Family and HCC-Related signaling pathways

The USP family is the largest DUB family (Xiong et al. 2022; Gao et al. 2023), with USP7, USP22, and USP28 playing crucial roles in HCC (Table 1). In wild-type p53 cells, USP7 mainly promotes the ubiquitination and degradation of p53 indirectly by deubiquitinating and stabilizing MDM2, thereby inhibiting the p53-mediated tumor suppressive effect(Saha and Ghosh 2025). In the context of p53 mutant types, USP7 tends to deubiquitinate and stabilize various oncoproteins such as N-Myc, directly promoting tumor progression(Tavana et al. 2018). USP22 exhibits similar functions in HCC, influencing the characteristics of cancer stem cells by regulating the stability of multiple proteins (Ling et al. 2020; Shan et al. 2024; Zeng et al. 2023). USP28 continuously activates the Wnt signaling axis by enhancing the expression of TCF7L2 (Sun et al. 2022). USP10 stabilizes the expression of SMAD family member 4 (Smad4) by inhibiting its ubiquitination and degradation, thereby activating the TGF-β pathway and promoting HCC cell migration (Yuan et al. 2020). Researchers performed RNA sequencing on HCC cell lines resistant to lenvatinib and found that USP14 expression was the most significantly altered. Further RNA sequencing after USP14 knockdown revealed calcium and integrin binding 1 (CIB1) as the most significantly changed molecule. Immunoprecipitation experiments confirmed their interaction, and USP14 was found to activate the p21 protein-activated kinase 1 (PAK1)-ERK1/2 signaling axis by reversing CIB1 ubiquitination, thereby maintaining lenvatinib resistance (Xu et al. 2024). Subcutaneous xenografts in lenvatinib-resistant mice regained sensitivity to lenvatinib following local injection of adeno-associated virus (AAV) with shCIB1, providing new insights into the lenvatinib resistance mechanism. Another study on USP20 showed that it suppresses the ubiquitination and degradation of HIF-1α, upregulates its expression level, and activates the HIF-1α pathway to promote tumor angiogenesis (Park et al. 2013). These studies suggest that targeting USP14 could represent a novel method for managing HCC.

Table 1.

Summary of USP family members and corresponding mechanisms

USP Family Member	Related Signaling Pathway/Axis	Substrate/Downstream Molecule	Effect/Outcome	Experimental Methods/Key Findings
USP7(Su et al. 2024)	p53 stabilization	p53	Inhibit tumorigenesis	Removal of p53 ubiquitin chains
	Stabilization of other oncoproteins	Oncoproteins	Promote tumor progression	-
USP22(Ning et al. 2022; Li et al. 2022)	Regulation of protein stability	Multiple targets	Influence cancer stem cell properties	-
	-	ABCC1	Sorafenib resistance	USP22 knockout reduces ABCC1 expression; IHC shows positive correlation in resistant samples
	-	E2F6	Activate PKB, promote HCC progression	USP22 knockout upregulates DUSP1, inhibits PKB activity
USP28(Sun et al. 2022)	Wnt signaling pathway	TCF7L2	Promote tumorigenesis	Inhibitor treatment in xenograft model reduces tumor size and TCF7L2 protein
USP10(Yuan et al. 2020)	TGF-β pathway	Smad4	Promote HCC cell migration	Inhibits Smad4 ubiquitination and degradation
USP14(Xu et al. 2024)	PAK1-ERK1/2 axis	CIB1	Maintain lenvatinib resistance	USP14 knockout alters CIB1 expression; AAV-shCIB1 restores drug sensitivity
USP20(Park et al. 2013)	HIF-1α pathway	HIF-1α	Promote tumor angiogenesis	Inhibits HIF-1α ubiquitination and degradation
USP8(Tang et al. 2023a)	Wnt/β-catenin/GPX4 axis	β-catenin	Inhibit ferroptosis	Knockout increases ROS, decreases GSH and GPX4
	-	OGT, SLC7A11	Inhibit ferroptosis	Stabilizes OGT and SLC7A11, enhances cystine uptake, reduces lipid ROS
USP1(Wang et al. 2022a)	-	c-Kit	Promote HCC progression, enhance lenvatinib toxicity	Knockout of c-Kit reverses USP1 oncogenicity
USP2a(Xiong et al. 2021)	-	RAB1A	Promote proliferation, migration, invasion	Inhibits RAB1A degradation
USP27(Zou et al. 2022)	-	SETD3	Promote migration and invasion	Inhibits SETD3 degradation
USP40(Wu et al. 2024)	-	CLDN1	Promote proliferation, migration, stemness	Inhibits CLDN1 ubiquitination
USP11(Qiao et al. 2021)	-	KLF4 (K63-linked)	Promote proliferation and tumorigenesis	Disrupts K63 chains, leading to KLF4 degradation
	E2F1-USP11 positive feedback loop	E2F1	Inhibit autophagy, promote HCC progression	Stabilizes E2F1, activates ERK/mTOR pathway
CYLD (Regamey et al. 2003; Minderman et al. 2023)	NF-κB pathway	TRAF2, TRAF6, TRIP, TAK1	Inhibit NF-κB activation	Interacts with TRIP and TRAF2 to stabilize TRIP, suppress NF-κB hyperactivation

USP and ferroptosis

USP8, a member of the DUB family, stabilizes β-catenin expression through deubiquitination. Knockdown of USP8 expression increases lipid ROS levels while decreasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) protein levels (Li et al. 2024a). Studies suggest that USP8 may inhibit ferroptosis through the Wnt/β-catenin/GPX4 axis. Another study showed that USP8 stabilizes O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) expression, increasing the glycosylation level of solute carrier family 7 member 11 (SLC7A11), enhancing cellular cystine uptake, and inhibiting lipid ROS levels, thereby inhibiting ferroptosis (Tang et al. 2023b). This multi-level regulatory mechanism reflects the complexity of the ferroptosis signaling pathway, suggesting that targeting USP8 may enhance the sensitivity of tumor cells to ferroptosis inducers by interfering with the entire ferroptosis defense network. Blocking or removing USP8 pharmacologically has been shown to halt HCC progression and trigger ferroptosis by reducing OGT stability (Tang et al. 2023b). However, the partial restoration of intracellular GSH and lipid ROS levels by OGT or SLC7A11 overexpression implies that additional proteins regulated by USP8 and OGT could be involved in resisting ferroptosis.

USP and HCC Drug resistance

Expression of USP22 and ABCC1 is significantly elevated in sorafenib-resistant HCC cell lines, and knockdown of endogenous USP22 significantly reduces ABCC1 expression in these cells (Chang et al. 2022). Immunohistochemical analysis of HCC tissues indicated a positive link between USP22 and ABCC1 expression in sorafenib-resistant samples, which was absent in sorafenib-sensitive ones. Therefore, targeting USP22 might be a strategy to overcome resistance to sorafenib. Another study showed that USP22 mediates the deubiquitination of E2F transcription factor 6 (E2F6), upregulating its expression level and leading to transcriptional inhibition of dual specificity phosphatase 1 (DUSP1). Decreased DUSP1 levels can activate protein kinase B (PKB), promoting HCC progression (Jing et al. 2021). USP1 is highly expressed in HCC, and receptor tyrosine kinase (RTKs) gene family-encoded protein c-Kit has been identified as its downstream target using immunoprecipitation. Knockdown of c-Kit reverses the oncogenic effects of USP1 in HCC cells (Wang et al. 2022a). When HCC cells overexpressing USP1 were cultured in different doses of lenvatinib, lenvatinib exhibited higher inhibitory effects on these cells. This study not only demonstrated that USP1 promotes HCC progression as an oncogene but also enhances the toxicity of lenvatinib to HCC cells by stabilizing c-Kit expression, exerting a dual effect on HCC.

USP and HCC Malignant phenotypes

Studies have shown the significantly high expression of USP2a in HCC tissues, which is positively correlated with poor prognosis (Zhang et al. 2023b). RAB1A, a main regulator of endoplasmic reticulum and Golgi vesicle transport systems, potentially targets to USP2a in HCC cells. USP2a prevents RAB1A degradation through deubiquitination, leading to HCC cell proliferation, metastasis, and invasion (Xiong et al. 2021). USP7 upregulates the protein expression level of its downstream target molecule basic transcription factor 3 (BTF3) by inhibiting its degradation, promoting HCC cell stemness, and leading to epithelial-mesenchymal transition (EMT) (Hu et al. 2024). Zou et al. found that increased USP27 expression in HCC tissues is linked with poor prognosis (Xie et al. 2025). USP27 promotes HCC migration and invasion by inhibiting the ubiquitination and degradation of SET domain-containing 3 (SETD3), a member of the histidine methyltransferase family (Zou et al. 2022). Wu et al. indicated the elevated USP40 expression in HCC, while knockdown of USP40 can suppress HCC cell proliferation, metastasis, and stemness, while USP40 overexpression has the opposite effect. Claudin1 (CLDN1) is a downstream target of USP40, and USP40 stabilizes CLDN1 protein by inhibiting its ubiquitination, thereby exerting an oncogenic effect (Wu et al. 2024).

USP and substrate mutual promotion

In the ubiquitin–proteasome system, proteasomal degradation is the main function of K48-linked ubiquitin chains in regulating protein levels, while K63-linked ubiquitin chains primarily manage protein interactions, localization, and enzymatic activity (Tracz and Bialek 2021; Wang et al. 2022b). KLF4, considered a tumor suppressor, has decreased stability due to the disruption of K63-specific ubiquitin chains by USP11, leading to reduced the expression of KLF4 and mediating cell proliferation and tumorigenesis in HCC(Wang et al. 2025b; Yang et al. 2021). Qiao et al. showed that USP11 interacts with E2F transcription factor 1 (E2F1), enhancing its stability by inhibiting its ubiquitination and degradation. E2F1 also upregulates USP11 expression as its transcription factor, forming a positive feedback loop that inhibits autophagy and promotes HCC progression through the ERK/mTOR pathway (Qiao et al. 2021). Therefore, whether deubiquitinating enzymes stabilize the expression levels of downstream target molecules depends on their sites of action. USP family members can directly or indirectly activate HCC-related signaling pathways, enhance ferroptosis resistance, affect HCC drug resistance, and promote malignant phenotypes by acting on different downstream target molecules, different ubiquitination linkage sites, and different signaling pathways. These findings support that the USP family plays a crucial role in HCC progression, suggesting that discovering new targets regulating HCC progression centered on the USP family could be potential therapeutic strategies.

CYLD and NF-κB Signaling pathway inhibition

CYLD, a DUB(Massoumi 2011; Mukherjee et al. 2020), negatively regulates NF-κB signaling pathway activation by targeting signaling molecules such as TRAF2, TRAF6, TRIP, and TAK1 (Chen et al. 2022b; Bhardwaj et al. 2025; Reiley et al. 2007; Jono et al. 2004; Regamey et al. 2003). The ubiquitin-specific protease domain of CYLD is crucial for its interaction with TRIP and TRAF2, contributing to TRIP stabilization and suppression of NF-κB activation. When CYLD expression is downregulated, negative mutants of TRAF2 and TRAF6 inhibit CYLD expression, leading to persistent activation of the NF-κB signaling axis(Suenaga et al. 2019; Lee et al. 2013). Inflammation-related factors such as IKK and TRAF6 also play important roles in the occurrence and development of HCC (Chang et al. 2025). IKK activation is primarily regulated by phosphorylation of its upstream kinases. In HCC, abnormal IKK activation may induce persistent activation of the NF-κB signaling axis, thereby promoting inflammation and tumorigenesis (Napetschnig and Wu 2013; Karin and Ben-Neriah 2000). TRAF6 stability is regulated by its own ubiquitination. In HCC, abnormal expression or increased stability of TRAF6 may lead to persistent activation of inflammatory responses (Li et al. 2016; Wu et al. 2020), thereby promoting tumorigenesis. Additionally, CYLD deficiency or dysfunction impairs TRIP function (Regamey et al. 2003) and increases the activity of TAK1 and its downstream kinases (Reiley et al. 2007), further promoting sustained NF-κB activation. Downregulation of CYLD expression is closely corelated to the occurrence, development, invasion, and prognosis of various cancers, such as breast cancer, HCC, colorectal cancer, and OSCC. Its downregulation is also associated with sensitivity to chemotherapy and radiotherapy and prognosis (Suenaga et al. 2019).

The association between ubiquitination-related pathways and HCC progression

Ubiquitination medicates diverse signaling pathways, and its dysregulation is intimately linked to the initiation and progression of HCC. Mechanisms such as the dysregulation of ubiquitin-mediated degradation in the Wnt/β-catenin signaling axis, abnormal ubiquitination regulation in the NF-κB signaling pathway, ubiquitination of PTEN in the PI3K/AKT/mTOR pathway, and ubiquitination of LATS1/2 and YAP activation in the Hippo/YAP pathway all play significant roles in the progression of HCC. In-depth investigation of the regulatory mechanisms of these ubiquitination-related pathways can facilitate the advancement of novel HCC treatment strategies and improve patient prognosis.

Wnt/β-catenin signaling pathway

The Wnt/β-catenin signaling contributes to the initiation and advancement of HCC (Fig. 4). One of the important mechanisms underlying HCC development is the dysregulation of β-catenin ubiquitination and degradation. Under normal circumstances, β-catenin is phosphorylated by the Axin and GSK-3β complex, subsequently recognized and ubiquitinated by the E3 ubiquitin ligase β-TrCP, and ultimately degraded by the proteasome. However, the presence of Wnt ligands prevents β-catenin phosphorylation, allowing it to stabilize and build up in the cytoplasm, and then enter the nucleus to activate downstream target genes.

Fig. 4.

Mechanistic Role of the Wnt/β-catenin signaling pathway in Ubiquitination

In HCC, inhibition of β-catenin ubiquitination and degradation results in its abnormal accumulation in the nucleus, promoting the Wnt/β-catenin signaling axis in cell proliferation and tumor progression (Zhang et al. 2025; Teng et al. 2025). For example, USP39 enhances the stability of β-catenin by removing ubiquitin and prevents the maturation of TRIM26 E3 ligase mRNA precursors, reducing β-catenin ubiquitination and thereby promoting HCC progression (Wang et al. 2023b). Additionally, miR-199b-3p inhibits the Wnt/β-catenin signaling axis by targeting CCDC88A, thereby inhibiting the proliferation and invasion of HCC cells (Zhu et al. 2023).

NF-κB signaling pathway

The NF-κB signaling pathway plays a key role in inflammation and immune responses, and its abnormal activation is closely associated with the occurrence and development of HCC. Ubiquitination plays an important role in the regulation of the NF-κB signaling pathway, particularly in the activation process of the IKK complex. The IKK complex, composed of IKKα, IKKβ, and NEMO, depends on ubiquitination of TANK-binding kinase 1 (TBK1) and IκB kinase γ (IKKγ) for its activation (Hauenstein et al. 2017).

In HCC, abnormal activation of the NF-κB signaling axis can occur via various mechanisms, such as inhibiting ubiquitination and degradation of IκB, leading to the accumulation of NF-κB in the nucleus and activation of downstream inflammation-related genes (Yang et al. 2013). This abnormal activation not only improves the proliferation and survival of HCC cells but also enhances tumor invasiveness and drug resistance.

PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR signaling axis functions in cell growth, metabolism, and survival (Tian et al. 2023a). PTEN is a major negative regulator of the PI3K/AKT/mTOR axis, and its loss of function or inhibition leads to overactivation of AKT and mTOR, promoting the occurrence and development of HCC (Cheng et al. 2021).

Ubiquitination of PTEN is one of the important mechanisms regulating its function. For example, the E3 ubiquitin ligase FBXW10 ubiquitinates PTEN and boosts its degradation, thereby activating the PI3K/AKT/mTOR axis (Sahay et al. 2023; Luo et al. 2020). Furthermore, PTEN deletion or mutation is common in HCC, leading to continuous promotion of the PI3K/AKT/mTOR axis and facilitating metabolic reprogramming and proliferation of tumor cells (Fig. 5) (Liu et al. 2017).

Fig. 5.

Mechanistic Role of the PI3K/AKT/mTOR signaling pathway in Ubiquitination

Hippo/YAP Pathway

Tissue regeneration and tumor suppression heavily rely on the Hippo signaling pathway. YAP (Yes-associated protein) is the main effector of the Hippo signaling pathway (Ibar and Irvine 2020; Fang et al. 2025), and its activity is negatively regulated by LATS1/2 kinases. LATS1/2 phosphorylates YAP, promoting its retention and degradation in the cytoplasm (Moroishi et al. 2016).

In HCC, ubiquitination and degradation of LATS1/2 lead to abnormal activation of YAP, promoting proliferation and invasion of tumor cells (Shi et al. 2023; Valero et al. 2015; Hou et al. 2025). For instance, CKAP4 enhances endoplasmic reticulum autophagy and HCC progression by inhibiting K48-linked ubiquitination of RETREG1 (Mo et al. 2024). Additionally, abnormal activation of YAP can activate downstream target genes by binding to TEAD transcription factors, promoting the occurrence and development of HCC(Lin et al. 2024a).

Clinical relevance of ubiquitination regulation and HCC

Ubiquitination regulation contributes to the clinical diagnosis, treatment, and drug resistance of HCC. E3 ligases and deubiquitinases are regarded as potential clinical biomarkers for predicting the prognosis of HCC patients. Therapeutic strategies targeting the ubiquitination system, such as the advancement of small molecule inhibitors, Proteolysis-Targeting Chimeras‌ (PROTAC) technology, and deubiquitinase inhibitors, indicate new ideas for treating HCC(Teng et al. 2024). Furthermore, ubiquitination regulation also function in the drug resistance and immune treatment response of HCC. In-depth study of these mechanisms can help develop more effective treatment regimens and improve the prognosis of HCC patients.

Clinical biomarker potential of ubiquitination-related molecules

Ubiquitination-related molecules possess significant clinical biomarker potential in HCC. The expression levels of E3 ligases and DUBs are closely related to the prognosis of HCC (Bian et al. 2024; Tian et al. 2023b). For example, low-expressed FBXW7 is significantly linked with poor prognosis (Wang et al. 2015). Additionally, circulating ubiquitinated proteins, such as ubiquitinated p53, are also considered potential diagnostic biomarkers. Recent study conducted proteomic, phosphorylation modification omic, and ubiquitination omic sequencing and analysis on tumor and normal tissues from 85 HCC patients, finding that COL4A1, LAMC1, and LAMA4 were upregulated in patients with poor DFS (Lin et al. 2024b). Furthermore, the study revealed that TUBA1A, BHMT2, BHMT, and ACY1 exhibited different ubiquitination levels, closely related to poor prognosis in HCC patients (Lin et al. 2024b). The results imply that focusing on these proteins or their ubiquitinated versions could be advantageous for medical therapy.

Therapeutic strategies targeting the ubiquitination system

Therapeutic strategies targeting the ubiquitination system hold broad application prospects in HCC treatment. Small molecule inhibitors such as the MDM2 inhibitor Nutlin-3 and the proteasome inhibitor bortezomib have shown potential anti-tumor activities in preclinical studies of HCC. Nutlin-3 induces apoptosis and reverses epithelial-mesenchymal transition by blocking the MDM2-p53 interaction and activating the p53 pathway. Bortezomib regulates cyclin expression by inhibiting proteasome activity (Shi et al. 2015; Chen et al. 2011; Liao et al. 2023). However, the clinical efficacy of these two drugs in HCC patients has not been fully verified. Currently, there is a lack of Phase III clinical trial data to support their routine application in the treatment of HCC. Additionally, PROTAC technology, as an emerging targeted degradation technology, offers new avenues for HCC treatment by inducing target protein degradation using the intracellular natural ubiquitin–proteasome system (Chang et al. 2024; Wang et al. 2024b; Li et al. 2025).

The development of deubiquitinase inhibitors is also one of the current research hotspots. For example, compounds targeting USP7 inhibited the proliferation and migration of HCC cells (Liu et al. 2023). Furthermore, combined use of the AKT inhibitor capivasertib and the USP14 inhibitor IU1-248 can upregulate ubiquitination of TUBA1A K370, promote TUBA1A protein degradation, and thereby inhibit HCC growth (Lin et al. 2024b). Deubiquitination of the TUBA1A K370 site functions in the proliferation and transfer of HCCs. Targeting the AKT-USP14-TUBA1A complex can promote the degradation of TUBA1A and suppress the occurrence of liver cancer, providing a new molecular mechanism and therapeutic strategy for the precision medicine of HCC (Lin et al. 2025). Irpagratinib (ABSK011) is a highly selective FGFR4 inhibitor that blocks tumor proliferation by inhibiting the FGF19/FGFR4 pathway (Xie et al. 2023). Although the treatment strategy for HCC targeting UPS shows promising prospects, it still faces challenges such as drug resistance and toxic side effects. Future research should focus on developing more selective E3 ligase modulators, optimizing PROTAC design, exploring combination therapy regimens, and deeply tapping the therapeutic potential of DUBs. With a deeper understanding of the UPS regulatory mechanism, especially in combination with the molecular typing research of ubiquitination omics, more effective strategies will be provided for the precise treatment of HCC, which is expected to significantly enhance the prognosis of advanced HCC patients.

Frontier Research Directions and Challenges

Research on ubiquitination holds significant clinical value for the diagnosis, treatment, and drug resistance studies of HCC. The identification of novel ubiquitination processes, such as the exploration of the functions of non-canonical ubiquitin chains and their interactions with other post-translational modifications, provides novel perspectives for the molecular mechanisms of HCC. Ubiquitination regulation in the TME, especially the impact of ubiquitination in immune cells on HCC immune escape, provides a theoretical basis for developing new immunotherapy strategies. The development of precision medicine enables ubiquitination-targeted therapeutic strategies based on patient molecular subtypes.

Discovery of novel ubiquitination processes

In addition to the classical K48 and K63 ubiquitin chains, the functions of non-canonical ubiquitin chains are increasingly gaining attention. Due to its unique spatial structure and stable "occupation" characteristics, the K27 ubiquitin chain is believed to play crucial roles in DNA damage, immune responses, and protein homeostasis regulation (Kong et al. 2022; Wang et al. 2024c). However, specific deubiquitinases for K27 ubiquitin chains have yet to be discovered, and research on their assembly mechanisms and specific recognition domains is still in its early stages.

Complex interactions exist between ubiquitination and other PTMs like phosphorylation and SUMOylation. For example, SUMO-targeted ubiquitin ligases (STUbLs) play important roles in gene regulation, genome stability, embryonic development, and cancer (Chang and Yeh 2020; Ji et al. 2023). Furthermore, interactions between ubiquitination and modifications such as succinylation and lactylation also demonstrate significant regulatory functions in cell metabolism and immune responses (Wang et al. 2023c; Cheng et al. 2023).

Ubiquitination regulation in the tumor microenvironment

In TME, ubiquitination can regulate immune cell function. For example, E3 ubiquitin ligases function in tumor immunity by regulating immune cell activation, proliferation, and cytokine secretion, thereby affecting tumor immune escape (Shariq et al. 2023). Studies have demonstrated that ubiquitination can regulate the activated state of T cells, further changing their ability to recognize and remove tumor cells (Xiang et al. 2025). Low expression of T-cell-associated ubiquitinated genes such as UBE2E1 is associated with inhibition of HCC cell proliferation, suggesting a critical role in immune surveillance (Chen et al. 2024).

The COP9 signaling subunit 6 (CSN6) promotes tumor growth by antagonizing the E3 ligase SPOP, stabilizing HMGCS1 (a key enzyme in the mevalonate synthesis pathway), and activating the YAP1 signaling pathway (Li et al. 2024b). Mechanistically, CSN6 disrupts SPOP-mediated degradation of HMGCS1 ubiquitination by regulating the stability of MDM2, thereby enhancing cholesterol synthesis and tumor malignant phenotype. This finding reveals the role of ubiquitination as a bridge between dyslipid metabolism and HCC progression (Li et al. 2023; Chang and Ding 2018; Lai et al. 2025).

Conclusion and outlook

Ubiquitination functions in the occurrence, development, and drug resistance of HCC. Based on the regulation of Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and Hippo/YAP signaling pathways, ubiquitination influences cell proliferation, apoptosis, metabolism, and immune escape. For example, abnormal expression of E3 ubiquitin ligases and DUBs has a close relation to the prognosis of HCC, and their dysregulation can alter the stability of key intracellular proteins, thereby affecting tumor progression. Furthermore, ubiquitination is also involved in regulating immune cell function in the tumor microenvironment, impacting HCC immune escape.

Despite significant progress in targeted therapy and immunotherapy for HCC, numerous challenges remain. For instance, although targeted drugs such as sorafenib and lenvatinib have extended patient survival, their objective response rate (ORR) as well as progression-free survival (PFS) still need improvement. In immunotherapy, although combinations of immune checkpoint inhibitors and anti-angiogenic drugs have become the first-line treatment standard for advanced HCC, some patients still develop resistance. In the future, ubiquitination system-targeted therapeutic strategies are expected to emerge as new breakthrough directions. For example, by inhibiting the activity of E3 ligases or DUBs, protein homeostasis within tumor cells can be modulated, thereby affecting tumor proliferation and drug resistance. Additionally, developing individualized treatment regimens based on patient molecular subtypes through multi-omics technology is also an important direction for future HCC treatment(Qian et al. 2023).

Multi-omics integration and translational medical research are crucial for deepening our understanding of the molecular mechanisms of HCC and developing new treatment strategies. By the integration of multi-omics data, phosphorylationomics, and ubiquitinationomics, the molecular regulatory networks in HCC can be comprehensively revealed. For example, the application of ultra-high-resolution mass spectrometry aids in discovering new ubiquitination modification sites and regulatory pathways. Furthermore, CRISPR screening technology can systematically identify key ubiquitination regulatory genes in HCC. The combination of these technologies not only aids in discovering new therapeutic targets but also provides more precise guidance for clinical treatment. Translational medical research emphasizes rapidly transferring basic research results into clinical applications, validating the efficacy and safety of new treatment strategies through clinical trials. Therefore, multi-omics integration and translational medical research are important means for promoting precision treatment of HCC, potentially offering patients more treatment options and better prognoses.

Authors contributions

L W, H Z, Y H: Writing – original draft, review & editing. M L, H S, Y L: Writing – review & editing, Supervision, Project administration.

Funding

Not applicable.

Data availability

All data are provided within this manuscript.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed on the publication of this study.

Conflicts of interest

The authors declare no competing interests.