RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma

Abstract

Melanoma is an aggressive type of cancer that is prone to developing resistance to targeted therapies and immunotherapies, so it is necessary to seek novel therapeutic opportunities. RING finger E3 ubiquitin ligases (RNFs) play a crucial role in the ubiquitin–proteasome system and are important in regulating the development of melanoma by orchestrating various pathways. In this review, we analyze the structural and functional characteristics of the RNF subfamily to clarify their mechanisms of action in melanoma and to compare the functional differences among various RNFs. Additionally, we systematically evaluate potential therapeutic strategies targeting RNFs, including small-molecule drugs, proteolysis-targeting chimeras (PROTACs), and molecular glues, and further propose new directions for drug design by using computer-aided technology. Furthermore, this review suggests that RNF-targeted therapy should be combined with existing therapies, providing a novel approach for the precise treatment of melanoma, and is significant for clinical application and drug development.

Introduction

Melanoma is an aggressive malignancy that originates from melanocytes, with its global incidence exhibiting a rapid upward trend. While surgical intervention often cures early stage disease, metastatic melanoma carries an inferior prognosis [1–6]. The advent of targeted therapies and immune checkpoint inhibitors (ICIs) has transformed the treatment paradigm for melanoma, concurrently leading to the development of drug resistance in patients, creating a clinical treatment dilemma [7, 8]. This stark reality necessitates a shift in therapeutic strategies from targeting downstream effector pathways toward intervening in the regulation of upstream master regulators. Against this backdrop, the ubiquitin–proteasome system (UPS) is rapidly emerging as a new focal point in tumor biology and therapeutic development, serving as a pivotal regulatory node in cellular homeostasis and tumor biology.

Ubiquitination, as a pivotal post-translational modification, involves a trienzyme cascade comprising E1 (activating enzyme), E2 (conjugating enzyme), and E3 (ligase) enzymes. This process covalently tags ubiquitin molecules onto substrate proteins, thereby precisely determining their fate—whether proteasomal degradation, membrane transport, or signal transduction [9, 10]. Within this cascade, E3 ubiquitin ligases are responsible for substrate-specific recognition, constituting the core determinant of functional specificity within the ubiquitin pathway. Among E3 ligase families, the RING finger E3 ubiquitin ligases (RNFs) constitute the most populous category. Its hallmark really interesting new gene (RING) domain directly catalyzes the transfer of ubiquitin from E2 to the substrate [11]. Extensive research indicates that numerous RNFs are abnormally expressed in melanoma. Through ubiquitin modification, they precisely regulate core nodes in key signaling pathways, profoundly influencing tumor proliferation and metastasis, as well as therapeutic resistance [12–14]. It implies that the E3 ligase family not only serves as a pivotal hub in the malignant progression of melanoma but also, owing to the amenability of its catalytic and regulatory functions to intervention, represents a reservoir of novel therapeutic targets with immense potential.

This review examines the classification and structural–functional basis of RNFs, subsequently exploring their molecular mechanisms that drive melanoma initiation and progression through intricate signaling networks. Moreover, it focuses on evaluating drug development strategies targeting key RNFs. It highlights recent advances and challenges while projecting their translational potential for combination with existing therapies. We pioneer an exploration of its cross-regulatory mechanisms from a “network hub” perspective, comprehensively evaluating innovative targeting strategies such as proteolysis-targeting chimeras (PROTACs) and molecular glues, thereby providing novel therapeutic references for melanoma treatment.

RNFs are the architects of ubiquitin signaling

RNFs are defined by their zinc-coordinating RING domain, which recruits E2 enzymes to catalyze substrate ubiquitination [15, 16]. Based on domain architecture, RNFs are categorized into five subfamilies: the Tripartite Motif-containing (TRIM) family, RING-ubiquitin interaction motif E3 ligases (RING-UIM E3s) family, membrane-associated RING-CH (MARCH) family, Pseudoatutimmune transmembrane really interesting new gene E3 ubiquitin ligases (PA-TM-RING E3s), and RING-between-RING (RBR) family, whose structural differences dictate their diverse functions in substrate recognition and subcellular localization [12, 17].

The catalytic core and ubiquitin system integration

Despite the structural and functional diversity exhibited by these five subfamilies, they share several fundamental standard features as core members of the RNFs. First and foremost, they all possess a RING (or RING-CH, RING-H2 variant) domain, which forms the functional basis of their E3 ubiquitin ligase activity (Fig. 1). This domain adopts a specific spatial conformation through its unique zinc ion coordination pattern, enabling it to recruit and bind E2 ubiquitin-conjugating enzymes—a crucial step in initiating the ubiquitinylation cascade [18–20]. Consequently, they collectively participate in the ubiquitin–proteasome system. By catalyzing the ubiquitin modification of substrate proteins, they play a central role in regulating protein stability, activity, localization, and interactions. In turn, this profoundly influences a series of fundamental biological processes, including the cell cycle, signal transduction, stress responses, and immune responses.

Fig. 1.

A schematic diagram comparing the architectural features and functional scope of five distinct types of RNFs

Defining the functional specialization of RNFs subfamilies

The five RNF subfamilies diverge in domain architecture, catalytic mechanism, localization, and functional specialization. Catalytically, the RBR family employs a two-step, homologous to E6-AP C-terminus (HECT)-like mechanism involving a cysteine intermediate, whereas the other four subfamilies (TRIM, RING-UIM, MARCH, and PA-TM-RING) are canonical RING-type E3s that directly transfer ubiquitin from E2 to substrate [21, 22] (Table 1). Structurally, TRIM proteins feature a cytoplasmic/nuclear triad motif; RING-UIM members contain ubiquitin-interacting motifs for chain editing; MARCH and PA-TM-RING are membrane-associated, with the former regulating immune-related turnover and the latter modulating endocytic signaling [12]. Functionally, the subfamilies specialize in innate immunity (TRIM), DNA repair and immune signaling (RING-UIM), membrane protein turnover and immune evasion (MARCH), receptor endocytosis and T cell tolerance (PA-TM-RING), and mitochondrial quality control (RBR) [40–42]. These distinctions underpin the functional diversity and regulatory network of RNFs.

Table 1.

Structure, function, and physiological roles of the RNFs in melanoma

RNFs	Structure	Function	Subcellular localization	References
TRIM	The N-terminal domain comprises a RING domain, one or two B-box domains, and a coiled-coil structure; the C-terminal domain incorporates diverse domains such as SPRY or phd-bromo, conferring multifaceted biological functions upon TRIM family proteins	Polymerization and chain selection: The coiled-coil structure of TRIM promotes dimerization/polymerization, thereby recruiting E2 enzymes via the RING domain and selecting K63 (signaling) or K48 (degradation) chain types Immune signaling hub: TRIM5α recognizes viral capsids and mediates their early degradation, while TRIM21 binds antibody–virus complexes, triggering NF-κB and IRF3 activation	Cytoplasm or nucleus, with some components entering PML nuclear bodies following SUMOylation	[23–29]
RING-UIM	In addition to the RING domain, it contains one or more ubiquitin-interacting motifs (UIMs), typically approximately 20 residues in length, which can directly bind to monoubiquitin or specific polyubiquitin chains	Chain editing and signal selection: The UIM domain can bind to ubiquitin of specific chain types and direct the extension or truncation of secondary ubiquitin chains, thereby switching between signaling and degradation fates Signal pathway regulation: RNF114 is recruited to DNA damage sites in an ADP-ribosylation-dependent manner, where it extends K11-linked polyubiquitin chains to influence DNA repair	Cytoplasm, nucleus, and membrane-associated regions; UIM regulates its interactions with endosomes or transcription complexes	[30–32]
MARCH	N-terminal RING domain (C4HC3 type) and multiple transmembrane helices (typically 2–4); lacking coiled-coil or B-box domains	Inflammation regulation: MARCH2 negatively regulates the NF-κB signaling pathway by targeting NF-κB essential modulator (NEMO) for proteasomal degradation via K48-linked polyubiquitination, thereby playing a crucial role in maintaining cellular anti-inflammatory homeostasis Viral escape mechanisms: MARCH2 and MARCH11 can target NEMO and other viral proteins, suppress interferon production, and enhance viral replication and dissemination	Endoplasmic reticulum, Golgi apparatus, endosomal membrane	[33–35]
PA-TM-RING	N-terminal protease-associated domain, single transmembrane helix, and C-terminal RING finger domain	Endosomal regulation: GRAIL (RNF128) targets CD3ε and other TCR components, mediating their polyubiquitination and degradation to regulate naïve T cell tolerance induction and Treg cell function; RNF13/167 recognizes substrates via its PA domain and releases its RING domain in early endosomes to execute ubiquitination Endosomal maturation and signal attenuation: PA-TM-RING members also regulate the sorting and degradation of EGFR and Notch receptors within endosomes, influencing growth factor signal intensity and persistence	Endomembrane of the endocytosis/secretory pathway	[36, 37]
RBR	Three modules: RING1–IBR (In-Between-RING)–RING2, wherein RING2 contains a catalytic cysteine; frequently accompanied by UBL or other regulatory segments	Two-step catalytic mechanism: RING1 recruits E2 ~ Ub, while RING2’s cysteine domain forms an intermediate before transferring Ub to the substrate. This dual RING–HECT functionality enables precise chain-type regulation Mitochondrial quality control: Parkin is selectively recruited to damaged mitochondria, promoting their autophagy to maintain cellular homeostasis	Cytoplasm, mitochondrial outer membrane	[38, 39]

In summary, this intricate division of labor enables RNFs to form a collaborative network that governs diverse cellular processes. In melanoma, dysregulation of this precise machinery leads to the co-option of distinct subfamilies for tumorigenesis, highlighting their role as critical nodes in pathogenic signaling.

Orchestrating oncogenic signaling: discrete roles of key RNFs in melanoma pathways

Following a systematic examination of the structural characteristics and functional roles of RNFs, a central question emerges: How do these proteins drive the malignant progression of melanoma? Within the complex intracellular milieu of melanoma, multiple signaling pathways interweave to form a sophisticated and dynamic regulatory network. Existing studies have identified several key RNFs that act as critical hubs within this network, integrating upstream oncogenic signals to precisely dictate downstream cell fate decisions, ultimately driving tumor progression, heterogeneity, and therapy resistance by orchestrating cross-talk among multiple pathways in melanoma cells. However, it is noteworthy that not all RNFs exert tumor-promoting effects in melanoma; certain key RNFs demonstrate tumor-suppressive functions within specific signaling contexts (Fig. 2).

Fig. 2.

Key RNFs, as the central regulatory node of multiple signaling pathways, promote the occurrence and development of melanoma

P53 signaling pathway and notch signaling pathway

P53 signaling pathway plays an important role in the complex intracellular environment of melanoma. Owing to the absence of cyclin-dependent kinase inhibitor 2A (CDKN2A)/ADP-ribosylation factor (ARF), p53 is often in a state of “functional loss” in melanoma, and restoring p53 function has become an important strategy. Mouse double minute 2 homolog (MDM2) is a key E3 ubiquitin ligase, and its N-terminal hydrophobic pocket can directly bind to p53, thereby inhibiting its transcriptional activity. At the same time, the C-terminal RING domain functions as an E3 ligase, recruiting E2 ubiquitin conjugates to promote p53 nuclear export and ubiquitin proteasome degradation [43, 44]. It is worth noting that p53 and MDM2 form an autoregulatory feedback loop: An increase in p53 levels can activate the transcription of MDM2, which in turn negatively feeds back to reduce p53 levels, forming a precise regulatory loop [45, 46]. In addition, MDM2 is also a downstream target of the Ras/Raf-MAPK pathway, suggesting that it may mediate the inhibition of p53 activity by Ras oncogenic signaling [47]. Further research has confirmed that MDM2 antagonists can enhance the antitumor effect of MAPK/extracellular signal-related kinase (ERK) inhibitors in melanoma, highlighting their potential for combination therapy [48].

In addition to regulating the p53 pathway, MDM2 also participates in the transduction of Notch signaling; the abnormal activation of Notch1/4 also promotes the progression of melanoma. The specific mechanisms are as follows: On the one hand, MDM2 degrades the Numb protein through ubiquitination, thereby relieving Numb’s inhibitory effect on the Notch signal and indirectly enhancing it; on the other hand, it can directly stabilize and activate the intracellular domain (NICD) of Notch1 [49, 50]. These interactions together form the “p53–MDM2–Numb” regulatory axis, which coordinates the functions of the two key pathways, p53 and Notch (Fig. 3A) [44, 49]. Some studies suggest that Notch4 may serve as a substrate for MDM2 degradation, and its degree of degradation is negatively correlated with intracellular p53 levels [51, 52]. Therefore, targeting MDM2 to restore the p53 pathway and regulate Notch signaling simultaneously provides a new approach for treating melanoma with dual pathway dysregulation.

Fig. 3.

Mechanisms of action of different RNFs in different pathways. A Mechanisms by which MDM2 and MDMX modulate the Notch and p53 pathways. B Mechanisms by RNF128 and RNF43 modulate the Wnt/β-catenin signaling pathways. C Mechanism of RNF2 regulation of the TGF-β pathway. D Mechanism of action of TRIM28/TRIM17 in modulating the JUNB pathway. E Mechanisms by which TRIM14 and RNF157 modulate the PI3K/AKT and MAPK pathways. F Mechanisms by which c-CBL and RNF114 modulate other pathways in melanoma

Murine double minute X (MDMX), as a homologous protein of MDM2, is highly similar in structure and function, but there are also key differences [53]. Clinical studies have shown that approximately 65% of stage I–IV human melanomas have upregulated expression of MDMX. In a mouse melanoma model driven by the neuroblastoma RAS viral oncogene homolog (NRAS) oncogenes, melanoma-specific overexpression of MDMX significantly promotes tumorigenesis [54]. Unlike MDM2, MDMX does not possess E3 ligase activity and cannot directly mediate the ubiquitination degradation of p53. Instead, it directly inhibits the transcriptional activity of p53 through its N-terminal p53 binding domain. MDMX can also form heterodimers with MDM2 through its RING domain, which enhances the stability of MDM2 and synergistically strengthens the inhibition of p53 transcriptional activity and ubiquitination degradation efficiency, forming a stronger p53 negative regulatory module [55, 56]. These findings collectively establish MDMX as an important potential target for combination therapy of melanoma.

In summary, MDM2 and its homolog MDMX form the central coregulatory module within the p53 pathway, making MDM2/MDMX a key hub linking the p53, MAPK, and Notch pathways. This role as multi-pathway integrators explains why single-pathway inhibitors, such as those targeting MAPK/ERK, are prone to resistance, as inhibition of one pathway may be compensated by concurrent or enhanced signals from others. Consequently, targeting MDM2/MDMX holds significant preclinical promise, as their antagonists can simultaneously reactivate p53 function, disrupt Notch signaling, and potentially enhance the efficacy of MAPK-targeted therapies, offering a novel strategy for dual or even multi-pathway combination treatment.

Wnt/β-catenin signaling pathway

Wnt/β-catenin signaling pathway is the key hub to promote melanoma metastasis [57]. Unlike the cancer-promoting effect of the MDM protein family, RNF128 (GRAIL) and RNF43 function as complementary negative regulators of Wnt signaling in melanoma, albeit through distinct molecular mechanisms. RNF128 exerts its tumor-suppressive role by the expression of CD44 and cortactin (CTTN), thereby inhibiting canonical Wnt/β-catenin signaling. However, in melanoma, the expression of RNF128 is generally significantly downregulated. The downregulation of RNF128 can promote the ubiquitination and degradation of CD44 and CTTN, activate β-catenin target genes (such as c-myc), and promote epithelial mesenchymal transition (EMT) [58]. Its frequent downregulation in melanoma, in addition to this inhibition of the Wnt pathway, promotes the development of an aggressive phenotype. In contrast, RNF43 primarily targets the noncanonical Wnt pathway by mediating ubiquitination and degradation of VANGL2, then promoting clathrin-dependent endocytosis of ROR1/ROR2 receptors, thus blocking WNT5A-induced invasion and BRAF/MEK inhibitor resistance (Fig. 3B) [59, 60].

Together, this positive–negative regulatory paradigm reveals part of the molecular basis for melanoma heterogeneity. Low RNF128 expression is associated with enhanced invasiveness, while loss of RNF43 function is linked to drug resistance and invasion. Together, they form a cooperative inhibitory network constraining both major branches of Wnt signaling. Their frequent downregulation represents a key escape mechanism for melanoma cells, highlighting the potential therapeutic value of restoring their activity to suppress metastasis and overcome targeted therapy resistance.

TGF-β signaling pathway

The TGF-β signaling pathway directly regulates the expression of genes related to cell invasion and migration, and RNF2 is a key epigenetic regulatory factor in TGF-β signaling. Overexpression of RNF2 directly inhibits the transcription of latent transforming growth factor β-binding protein 2 (LTBP2) through the ubiquitination of histone H2A lysine 119 (H2AK119), thereby leading to subsequent gene silencing [61]. Although studies have shown that LTBP protein can bidirectionally regulate the TGF-β signaling pathway [62], during the process of melanoma invasion, downregulation of LTBP2 can lead to the upregulation of TGF-β signaling in reverse, thereby promoting the metastasis and invasion of melanoma. On the contrary, RNF2 drives proliferation by directly upregulating the transcription of cell cycle regulator cyclin D2 (CCND2) (Fig. 3C) [61].

JUNB signaling pathway

JUNB signaling pathway can regulate the proliferation and invasion of melanoma. As a key regulator of the JUNB signaling pathway, TRIM28 plays a crucial role in maintaining self-renewal, regulating the balance between melanoma invasiveness and growth [63, 64]. Research shows that knockdown of TRIM28 in melanoma can enhance its invasion, which may be related to the upregulation of growth-promoting factors such as C–X–C motif chemokine ligand 2 (CXCL2) and interleukin 8 (CXCL8) following TRIM28 deletion [65]. Additionally, TRIM17 promotes melanoma cell proliferation by downregulating TRIM28 expression, which in turn inhibits the ubiquitination and degradation of anti-apoptotic proteins (Fig. 3D). Overexpression of TRIM28 or inhibition of TRIM17 can restore the sensitivity of melanoma to targeted therapy [66]. In melanoma, TRIM28 also extensively affects gene expression by regulating transcriptional elongation, including the negative regulation of RNA polymerase II elongation to inhibit JUNB expression [67]. JUNB, as a key regulatory protein, directly inhibits Yes-associated protein 1 (YAP1) expression and activates growth-promoting factors, such as CXCL8, thereby cooperatively regulating the dynamic balance between melanoma invasion and growth via TRIM28 (Fig. 3D) [65]. In general, TRIM28 influences the biological behavior of melanoma through various mechanisms, and its role in the JUNB pathway extends beyond any single signaling pathway.

Furthermore, the antagonistic relationship between TRIM28 and TRIM17 in regulating the stability of anti-apoptotic proteins adds another layer to their networked role in determining cell fate. However, the specific mechanism by which TRIM28 regulates gene expression in different types of cancer requires further research.

PI3K/AKT and MAPK signaling pathway

The phosphoinositide 3-kinase (PI3K) and MAPK signaling pathways are implicated in regulating multiple processes during melanoma development, such as tumor cell growth and proliferation. In melanoma, TRIM14 is frequently overexpressed and promotes the sustained activation of the PI3K/AKT and STAT3 signaling axes by facilitating ubiquitin-mediated degradation of PTEN, thereby enhancing melanoma cell proliferation, invasion, and epithelial–mesenchymal transition (Fig. 3E) [68, 69]. Similarly, RNF157 functions as a signal integrator downstream of the PI3K and MAPK pathways. Phosphorylation at its Ser660–663 residues, induced by PI3K or MEK activation, enables RNF157 to interact with the APC/C–CDH1 complex. This interaction establishes a “timed” degradation mechanism during late mitosis and the G1 phase, linking persistent oncogenic signaling with cell cycle progression (Fig. 3E) [70, 71]. Together, TRIM14 and RNF154 illustrate how RNFs coordinate upstream signaling with downstream metabolic and proliferative outputs to optimize melanoma cell growth.

Contrary to the oncogenic effect of the TRIM14, Parkin plays a suppressive tumor role in melanoma. Its expression is negatively regulated by the MAPK pathway: BRAF-V600E mutation downregulates its direct transcription target ETS transcription factor ELK1 (ELK1) through extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, thereby inhibiting Parkin transcription. Therefore, Parkin expression levels are lower in BRAF/NRAS mutant melanoma. Functionally, overexpression of Parkin can inhibit the in vitro and in vivo growth of melanoma cells and induce apoptosis, while its deletion or mutation (such as Parkin-e28k) can eliminate this anticancer effect [72, 73]. Parkin’s anticancer function is closely related to its regulation of mitochondrial quality control and induction of apoptosis. Clinical data also show that Parkin is highly expressed in wild-type BRAF/NRAS melanoma, suggesting that its agonists may provide new treatment options for specific subtypes of melanoma [72].

Other pathways

In addition to the abovementioned signaling pathways, several distinct regulatory mechanisms contribute to the initiation and progression of melanoma. Among these, c-CBL, a multifunctional E3 ubiquitin ligase, is highly expressed in melanoma and facilitates tumorigenesis through multiple mechanisms. On the one hand, c-CBL directly interacts with kinases such as steroid receptor coactivator (SRC) to form complexes that enhance FAK–SRC signaling output, thereby driving melanoma migration and invasion. On the other hand, c-CBL sustains the FAK–GRB2–SRC signaling axis, providing continuous molecular support for melanoma growth, proliferation, and motility (Fig. 3F) [74].

RNF114 is an atypical RING domain E3 ubiquitin ligase that maintains DNA repair homeostasis in melanoma by regulating the degradation of Poly (ADP-ribose) polymerase 1 (PARP-1). Inhibiting RNF114 prevents PARP-1 from detaching from DNA, leading to cell synthesis-induced cell death (Fig. 3F) [75]. Therefore, high expression of RNF114 is partially associated with a better prognosis, suggesting its potential role in maintaining cellular homeostasis or regulating immune function [75].

Implications of networked regulation and therapeutic prospects

The examples above clearly demonstrate that RNFs form an intricate regulatory network that tightly interconnects core melanoma signaling pathways, including p53, Wnt, Notch, MAPK/PI3K, and JUNB/YAP. Key RNFs such as MDM2/MDMX, RNF128/RNF43, and TRIM28 act as central nodes within this network; their dysregulation, whether overexpression or downregulation, disrupts network homeostasis and drives malignant progression.

This networked regulatory architecture has dual implications. On the one hand, targeting a single critical RNF node may produce multi-pathway synergistic effects through a “lever effect”; for example, an MDM2 inhibitor could concurrently influence the p53, Notch, and MAPK pathways. On the other hand, this network also exhibits redundancy and compensatory mechanisms, whereby inhibition of one node may activate others to sustain tumor survival, a feature that underscores the rationale for combination therapy.

Looking forward, therapeutic development targeting RNFs should adopt a systems biology perspective that accounts for their cross-talk networks. Strategies aimed at these proteins must fully consider their roles as network hubs. Promising avenues include combining MDM2/MDMX inhibitors with MAPK pathway inhibitors, restoring RNF43 function to overcome BRAF/MEK inhibitor resistance, and exploring TRIM28 modulators that suppress tumor growth without triggering invasion. A deeper understanding of how RNFs remodel signaling networks in specific genetic contexts, such as BRAF-mutant versus NRAS-mutant melanoma, will be essential for designing precise and effective combination therapies.

In summary, dissecting the signaling integration network mediated by RNFs not only deepens our understanding of melanoma pathogenesis but also provides a solid theoretical foundation for developing next-generation combination treatment strategies.

Therapeutic targeting: from small-molecule inhibition to novel degradation strategies

The preceding section systematically elucidated the core mechanisms by which RNFs act as hubs in melanoma signaling networks: By integrating multiple pathways, including p53, Wnt, MAPK and PI3K, they precisely regulate tumor cell proliferation, metastasis, immune evasion, and treatment resistance. These mechanistic characteristics establish RNFs not only as key drivers of tumorigenesis and progression but also as highly promising drug targets. However, unlike classical kinase inhibitors, strategies targeting RNFs must fully account for their unique structural features, particularly the transient protein–protein interactions mediated by the RING domain, as well as their functional properties as “multi-node regulators” within the network [7, 8, 76, 77]. Accordingly, this chapter systematically evaluates various intervention modalities targeting RNFs, ranging from traditional small-molecule inhibitors to emerging event-driven degradation technologies such as PROTACs and molecular glues, and explores the advantages, challenges, and therapeutic prospects of these strategies in the treatment of melanoma.

Pioneering targets: established intervention strategies and inhibitor development of RNFs.

Among the vast RNF family, a select few have emerged as “pioneering targets,” those for which the biological rationale is strongest, the mechanistic understanding is most mature, and consequently, the drug development efforts are most advanced. The journey of targeting these RNFs encapsulates the evolution of modern therapeutic modalities, beginning with conventional occupancy-driven inhibitors and expanding into the innovative paradigm of event-driven degradation (Table 2). In this section, we focus on three representative RNFs: MDM2/MDMX, the IAP family, and c-CBL. The experience gained from these targets provides a valuable foundation for addressing more challenging members of the family.

Table 2.

Therapeutic landscape of representative RNF inhibitors in melanoma: mechanisms of action and limitations

Target site	Existing inhibitors/candidate drugs	Activity values	Methods for measuring activity	Advantages	Limitations	Inhibitor types	Preclinical/clinical progress	References
MDM2	Alrizomadlin	IC50 = 8 µM Ki = 1 nM	WST-8 assay (HCT116)	Well-tolerated and possesses potential for combination therapy	High toxicity	Small-molecule inhibitor	Preclinical research	[78]
	Nutlin-3	Ki = 90 nM	Fluorescence Polarization assay	The first effective MDM2 small-molecule inhibitor	Low water solubility with high toxicity and side effects	Small-molecule inhibitor	Preclinical research	[79]
	RITA	GI50 = 0.8 μM Kd = 1.5 nM	MTT cell proliferation assay (HCT116)	Cell-permeable and specific	Potential side effects of metabolic byproducts	Small-molecule inhibitor	Preclinical research	[80]
	Navtemadlin	IC50 = 0.6 nM Kd = 0.045 nM	Homogeneous time-resolved fluorescence (HTRF)-binding assay/SPR	Precision and efficiency combined in MDM2	Short half-life	Small-molecule inhibitor	Preclinical research	[81]
	KT253	IC50 = 0.3 nM	MTT cell proliferation assay (RS411)	Highly effective with long-lasting results	Single administration route	PROTAC molecules	Clinical phase Ib study	[82]
	ALRN-6924	–	–	Dual inhibition of MDM2 and MDMX	Poor applicability	Peptide inhibitors	Phase II clinical study	[83]
	Idasanutlin	IC50 = 6 nM	Homogeneous time-resolved fluorescence (HTRF)-binding assay	Better efficacy and selectivity	High toxicity and potential drug resistance	Small-molecule inhibitor	Preclinical research	[84]
	MI 63	IC50 = 0.58 µM Ki = 3 nM	MTT cell viability assay (RH36)	Higher affinity and potential for combination therapy	Limited research, unknown side effects	Small-molecule inhibitor	Preclinical research	[85]
	Serdemetan	IC50 = 7.74 µM	MTT cell viability assay (HCT116)	Targets tumor cells that produce VEGF without affecting endothelial cells	Potential long-term harmful side effects	Small-molecule inhibitor	Preclinical research	[86]
	ATSP-7041	Ki = 8 nM	Fluorescence polarization assay (FPA)	High-efficiency cell penetration	Slow metabolism, increased risk of toxicity	Peptide inhibitors	Preclinical research	[87]
	Milademetan	IC50 = 21.9 nM	XTT cell Viability assay (SK-N-SH)	High specificity and safety	Limited clinical activity and susceptibility to drug resistance	Small-molecule inhibitor	Phase II clinical study	[88–90]
	Brigimadlin	IC50 = 21.1 pM	Alamar Blue assay (BT50)	High efficacy and long elimination half-life	No significant improvement in overall survival rate	Small-molecule inhibitor	Phase II clinical study	[91, 92]
TRIM21	(S)-ACE-OH	Kd = 17.9 µM	Isothermal titration calorimetry	Novel mechanism and high selectivity	Low safety and potential toxicity	Molecular glue	Preclinical research	[93]
TRIM24	dTRIM24	–	–	More efficient, more thorough	Potentially poor oral bioavailability	PROTAC molecules	Preclinical research	[94]
TRIM25	N6F11	–	–	Enhanced selectivity and activity	May trigger other compensatory mechanisms	Small-molecule inhibitor	Preclinical research	[95]
RNF2	PRT4165	–	–	Inhibits ubiquitin-dependent DSB repair	Limited selectivity and efficacy	Small-molecule inhibitor	Preclinical research	[96]
RNF114	Nimbolide	IC50 = 1.74 µM	Alamar Blue assay (B16)	Simultaneously inhibits multiple pathways	Poor solubility in water	Small-molecule inhibitor	Preclinical research	[97]

MDM2 and MDMX: a classic strategy for restoring p53 tumor suppressor function

Driven by a deep understanding of the MDM2–p53 interaction mechanism, significant progress has been made in developing drugs targeting this axis (Fig. 4). Among them, small-molecule inhibitors are primarily designed to mimic p53 residues Phe19, Trp23, and Leu26, competitively occupying the N-terminal binding pocket of MDM2 (residues 25–109). Nutlin-3, a pioneer in this class, blocks MDM2–p53 binding explicitly, induces p21 expression in a dose-dependent manner, and effectively establishes a G1 checkpoint leading to cell cycle arrest in p53 wild-type cells [98]. Unlike Nutlin, which targets the p53-binding domain of MDM2, serdemetan (JNJ-26854165) binds to the C-terminal RING domain of MDM2, thereby inhibiting the interaction between the MDM2–p53 complex and the proteasome and stabilizing p53 [99]. Notably, in p53-deficient contexts, it can also induce S-phase apoptosis by upregulating E2F1, thereby broadening its potential application. RITA (NSC 652287) acts through a distinct mechanism by targeting the N-terminal domain of p53, sterically hindering MDM2 binding and inducing conformational changes in p53 that preferentially activate potent pro-apoptotic genes [100].

Fig. 4.

Representative chemical structures of MDM2 inhibitors and schematic diagrams of their binding modes

Additionally, other structural classes of small molecules, such as the spiro-oxindole derivative MI-63, the chromenotriazolopyrimidine-based compound 9, and the isoindolinone derivative 74a, have demonstrated nanomolar-range antiproliferative activity and high dependency on the p53 pathway in preclinical studies, validating the generality of this strategy [101–103]^.

More recently, milademetan (DS-3032b/RAIN-32), a potent and selective oral small-molecule inhibitor of the MDM2–p53 interaction, has shown preclinical activity and phase II clinical efficacy in patients with MDM2-amplified, TP53 wild-type advanced solid tumors [89]. In addition, molecular docking analysis supported the binding of DS-3032B within the MDM2 p53-binding pocket, providing a structural basis for its antagonism of the MDM2–p53 interaction [88]. Given its dual role in coordinating p53, Notch, and MAPK pathways, MDM2/MDMX represents a rational therapeutic target, particularly for p53 wild-type melanoma where its inhibition can simultaneously restore tumor suppression and overcome resistance to MAPK-targeted therapies.

Beyond conventional small molecules, peptide inhibitors offer unique advantages in achieving dual-target inhibition. ALRN-6924, a structurally stabilized stapled peptide, exhibits high affinity for both MDM2 and MDMX p53-binding pockets, effectively relieving p53 suppression, and has advanced to phase II clinical trials [104]. Similarly, ATSP-7041 is another optimized peptide inhibitor that can simultaneously target MDM2 and MDMX [87].

In recent years, innovative intervention modalities have introduced new dimensions to target this axis. On the one hand, PROTACs have been successfully applied; for example, KT-253 links an MDM2 ligand to a ligand for another E3 ligase, forming a bifunctional molecule that directly induces the ubiquitination and degradation of MDM2 itself, leading to more thorough and potent activation of the p53 pathway [82]. On the other hand, strategies aimed at activating RING E3 ligases have also been explored. NSC 207895 is one of the few widely studied candidates in this category. It not only suppresses MDMX expression at both transcriptional and protein levels but also acts as a DNA-damaging agent; these dual mechanisms work synergistically to activate the p53 pathway strongly, ultimately inducing cancer cell cycle arrest and apoptosis [105].

In summary, through diverse strategies, including small-molecule antagonism, peptide inhibition, protein degradation, and even E3 ligase activation, targeting the MDM2/MDMX–p53 axis has emerged as a promising approach to restore p53 tumor suppressor function and treat p53 wild-type melanoma.

IAP family: targets for overcoming apoptosis resistance

Inhibitor of apoptosis proteins (IAPs) are overexpressed in various cancers, including melanoma, and contribute to therapy resistance by blocking caspase activation. Among the targeted strategies against IAPs, SMAC mimetics represent the most extensively studied class of antagonists. These small-molecule compounds mimic the endogenous N-terminal AVPI tetrapeptide motif of SMAC protein, competitively binding with high affinity to the BIR2 and BIR3 domains of IAPs, thereby relieving IAP-mediated inhibition of caspases 3, 7, and 9.

The field has evolved through multiple generations of candidate drugs: AT-406 (also known as SM-406 or Debio 1143), a second-generation, monovalent, and conformational constrained SMAC mimetic, demonstrates favorable oral bioavailability. In contrast, bivalent molecules such as SM-164 and Birinapant, which can simultaneously engage two BIR domains, more effectively promote the auto ubiquitination and degradation of IAPs, significantly enhancing TNF-α-dependent apoptotic signaling and exhibiting superior antitumor activity. Furthermore, GDC-0152, the first pan-IAP inhibitor to enter clinical trials, potently and simultaneously targets multiple BIR domains of XIAP, cIAP1/2, and ML-IAP [87, 102–104].

Recently, structure-based selective covalent inhibition strategies have introduced a breakthrough. Focusing on ML-IAP, which is specifically overexpressed in melanoma, researchers identified a highly conserved Lys135 residue within its BIR domain as a unique covalent-binding hotspot. Leveraging this insight, a series of small-molecule inhibitors incorporating reactive aryl sulfonyl fluoride (ArSF) “warheads” was developed. A representative compound, 142I5, selectively forms a stable sulfonamide covalent bond with ML-IAP (Lys135), thereby efficiently blocking its anti-apoptotic function. In SK-MEL-28 melanoma cell models, 142I5 successfully restored TNF-α-induced caspase-3/7 activity, confirming its potent pro-apoptotic capability [105]. By reactivating caspase-dependent apoptosis through SMAC mimetics or covalent targeting of ML-IAP, the IAP family offers a clinically actionable strategy to circumvent apoptosis resistance in melanoma, particularly in tumors with elevated IAP expression.

c-CBL: a pivotal hub for targeted immune regulation and signal transduction

As introduced in Sect. Other pathways, c-CBL is a multifunctional E3 ubiquitin ligase that facilitates melanoma tumorigenesis through multiple mechanisms. From a drug development perspective, the protein structure of c-CBL presents unique opportunities for allosteric intervention. Its architecture comprises a tyrosine kinase-binding (TKB) domain, a linker helix region (LHR), a RING finger domain, and a C-terminal regulatory tail. The dynamic interface between the TKB and LHR domains acts as a critical allosteric switch, controlling the transition of c-CBL from a “closed,” auto-inhibited state to an “open,” active state.

In recent years, conformation-stabilizing small-molecule inhibitors developed for its highly homologous family member, CBL-b, have provided a highly promising strategy for targeting c-CBL. Studies indicate that benzodiazepine and arylpyridone compounds can bind precisely to the TKB–LHR interface of c-CBL. They “lock” and stabilize the closed conformation of c-CBL through a series of key interactions, such as forming π–π stacking with Tyr363, hydrogen bonds with Tyr260 and Phe263, and a salt bridge network with the backbone of Glu268 [106–108]. This mechanism directly impedes the loading of the E2 ubiquitin-conjugating enzyme, thereby effectively inhibiting its E3 ligase activity. High-resolution crystal structures (e.g., PDB: 8QNG, 8GCY) have unambiguously revealed the binding mode of these inhibitors, providing a solid blueprint for structure-based drug optimization. Although these inhibitors were initially designed for CBL-b, the conformational locking strategy is considered equally applicable to c-CBL, given their high sequence conservation in the TKB–LHR–RING super domain.

This opens new avenues for targeting c-CBL in melanoma treatment, particularly in combination with immunotherapy. Targeting the auto inhibitory TKB–LHR interface of c-CBL with conformation-locking inhibitors provides a promising approach to suppress melanoma migration and invasion, with potential synergy when combined with immunotherapy due to c-CBL’s role in immune signaling.

Frontiers in drug discovery: emerging targets and innovative therapeutic modalities

Beyond established targeting strategies for MDM2/MDMX, IAPs, and c-CBL, many RNFs remain difficult to target using conventional small-molecule inhibitors owing to their structural uniqueness and functional complexity. This section focuses on the challenges posed by the druggability of such emerging targets. It highlights how innovative intervention modalities, notably molecular glues and PROTACs, offer novel pathways to overcome the “undruggable” nature of these proteins.

Druggability challenges and opportunities for emerging targets

Most members of the RNFs face significant “undruggability” challenges due to the inherent structural features of their RING domains. RNF157 serves as a representative example: Its catalytic domain lacks deep hydrophobic pockets that are typically amenable to small-molecule binding, and its E3 ligase activity strictly depends on phosphorylation at Ser660–663, which drives transient protein–protein interactions with the APC/C–CDH1 complex. This makes RNF157 particularly resistant to conventional occupancy-driven inhibitors.

A promising strategy to overcome such obstacles is illustrated by successful research on RNF114. By identifying a key residue, Cys8, at its substrate-recognition interface, researchers developed the natural product derivative nimbolide (Fig. 5A). This small molecule covalently modifies Cys8, irreversibly blocking the interaction between RNF114 and its substrate, PARP-1, thereby achieving highly selective inhibition of its E3 ligase function [75]. The covalent targeting of the substrate-recognition interface strategy offers an inspiring new approach for targeting E3 ligases, such as RNF157, that lack classical catalytic pockets.

Fig. 5.

Representative inhibitors targeting RNFs through distinct modalities and their mode of action diagrams: covalent inhibition, small-molecule antagonism, and molecular glues. A Representative chemical structures of inhibitors targeting RNF114. B Representative chemical structures of inhibitors targeting TRIM24. C Representative chemical structures of inhibitors targeting TRIM21

In contrast to the structural challenges exemplified by the above targets, specific RNFs present clearer druggable opportunities owing to their multi-domain architecture. For instance, TRIM24 contains not only a C-terminal RING domain but also a bromodomain and a PHD domain that recognizes histone modifications [109, 110]. These two epigenetic reader domains provide well-defined, relatively conventional small-molecule binding interfaces. On the basis of this, researchers have developed benzimidazolone-based small-molecule inhibitors that effectively disrupt TRIM24–chromatin binding (Fig. 5B) [111].

Nevertheless, many RING family members that play key roles in melanoma, such as MKRN2, still lack effective targeted inhibitors. The core obstacle lies in the inherent difficulty of targeting the RING domain itself and the transient nature of its functional protein–protein interfaces. Overcoming such targets will rely more heavily on event-driven strategies such as PROTACs and molecular glues, which are discussed in detail below. The successful covalent targeting of substrate-recognition interfaces (e.g., RNF114 Cys8) offers a generalizable strategy for engaging historically “undruggable” RING domain E3 ligases, expanding the actionable target space in melanoma.

Beyond conventional inhibition: principles and applications of molecular glues and PROTACs

To break through the “undruggability” bottleneck of RNFs, emerging event-driven intervention modalities, especially molecular glues and PROTACs, offer up-and-coming solutions. Instead of directly inhibiting enzymatic activity, these strategies reprogram the cell’s native ubiquitin–proteasome system to achieve selective degradation or functional modulation of target proteins.

Molecular glues are small molecules that induce novel interaction interfaces between an E3 ubiquitin ligase and a substrate protein, thereby bringing the substrate into proximity with the E3 for ubiquitination and degradation. An important proof-of-concept example is the (S)-ACE-OH (Fig. 5C). This case demonstrates the feasibility of developing molecular glues that engage RING E3 ligases and highlights their unique potential to exert therapeutic effects indirectly by degrading non-enzymatic functional proteins (Fig. 6).

Fig. 6.

Schematic of the proposed c-CBL PROTAC, which simultaneously binds to the TKB–LHR interface of c-CBL (gray) and recruits CRBN (light yellow), inducing ubiquitination (Ub) and proteasomal degradation of c-CBL

PROTAC technology utilizes bifunctional molecules: One end recruits an E3 ligase, while the other binds the target protein, thereby inducing ubiquitination and degradation of the target. This approach offers dual flexibility: First, it can be used to directly degrade oncogenic RNFs themselves (e.g., MDM2); second, it can cleverly hijack certain RNFs as “recruitment tools” to degrade other traditionally “undruggable” oncoproteins. This event-driven nature allows PROTACs to bypass the requirement for direct inhibition of the target’s catalytic activity, greatly expanding the targetable proteome in melanoma. By reprogramming the ubiquitin–proteasome system to selectively degrade oncogenic proteins, molecular glues and PROTACs represent a paradigm shift from occupancy-driven inhibition to event-driven elimination, greatly expanding the therapeutic repertoire for melanoma.

PROTAC strategies targeting MDM2/X: from mechanisms to prospects

The PROTAC technology enables differentiated therapeutic logic in targeting the p53–MDM2 pathway through the strategic selection of distinct E3 ligase ligands. For instance, KT-253 recruits an alternative E3 ligase (CRBN) to induce direct degradation of MDM2 [82]. In contrast, A1874 utilizes the MDM2 small-molecule inhibitor Nutlin as a ligand to recruit MDM2 itself, effectively “hijacking” its E3 ligase activity to ubiquitination and degrade an off-target protein, BRD4, while simultaneously stabilizing and activating p53 [112]. Alternatively, MD-224 adopts a “self-degradation” strategy by simultaneously recruiting the CRL4-CRBN E3 ligase and MDM2, designating MDM2 as the degradation substrate [113].

Looking forward, the development of PROTACs and molecular glues targeting MDM2/X can be advanced in three key directions: first, designing dual-target degraders capable of concurrently degrading both MDM2 and MDMX to enhance p53 pathway activation; second, incorporating covalent strategies to stabilize binding to key residues of MDM2/MDMX (e.g., Cys86 or Cys273), thereby improving degrader affinity and efficiency; and third, developing high-affinity molecular glues that optimize binding sites and conformational changes with MDM2 or MDMX to induce more effective protein degradation and enhance p53 activation. PROTAC-mediated degradation of MDM2 or MDMX achieves more complete and sustained p53 activation compared with conventional inhibitors, positioning this strategy as a next-generation approach for p53 wild-type melanoma with enhanced efficacy and resistance-prevention potential.

Innovative strategies targeting IAP and c-CBL: prospects and considerations

As E3 ligases, IAP family proteins are involved in multiple critical cellular processes, including resistance to apoptosis [114]. Designing molecular glues or PROTACs that degrade IAPs may interfere with their essential physiological functions in normal cells, potentially leading to undesired side effects. In comparison, SMAC mimetics competitively inhibit the anti-apoptotic function of IAPs without altering their overall protein levels, selectively relieving apoptosis inhibition and representing a currently more feasible and safer strategy. Owing to the central role of c-CBL in fundamental cellular processes and its associated toxicity risks, current drug development has focused mainly on CBL-b, leaving a gap in the development of highly selective c-CBL inhibitors.

Fortunately, CBL-b and c-CBL share high sequence conservation (approximately 86%) in the TKB–LHR–RING domains and exhibit similar conformational transitions and regulatory mechanisms. Studies have shown that specific CBL-b inhibitors can stably bind c-CBL by interacting with the TKB–LHR interface, locking the protein in an auto inhibited closed conformation—a mechanism akin to a “conformational glue” based on allosteric inhibition [115]. Structural biology further confirms that the key phosphorylation regulatory sites (CBL-b Tyr363/c-CBL Tyr371) and surrounding binding pocket residues are identical in both proteins.

Therefore, rational optimization based on CBL-b inhibitor scaffolds (such as arylpyridinones and benzodiazepines) represents a primary approach for developing c-CBL inhibitors. Future designs should retain core pharmacophores that interact with key residues (e.g., Tyr268, Phe271, and Glu276), while further exploring subtle differences in peripheral regions or dynamic conformations to enhance selectivity.

Building on these conformational control mechanisms, we propose two innovative degradation strategies: first, constructing heterobifunctional PROTAC molecules that utilize the core scaffold of CBL-b inhibitors to bind the TKB–LHR interface of c-CBL, stabilizing it in a closed conformation, while simultaneously recruiting exogenous E3 ligases (e.g., CRBN or VHL) to target c-CBL for degradation, achieving conformational locking and targeted elimination; second, designing homo-PROTACs that leverage c-CBL’s intrinsic RING-E3 activity, enabling inhibition in the closed state and inducing self-ubiquitination and degradation upon Tyr371 phosphorylation in the open state. This approach enables dual regulation through “activity inhibition” and “self-degradation,” under different signaling contexts, forming a state-adaptive negative feedback mechanism that combines the benefits of functional suppression and protein clearance.

For IAP and c-CBL, the development of state-adaptive PROTACs and conformation-locking inhibitors not only addresses the limitations of traditional antagonists but also provides a blueprint for targeting other RNFs with complex regulatory mechanisms and potential on-target toxicity concerns.

Conclusions and perspective

This review systematically elucidates the central role of RNFs in the signaling network of melanoma. These proteins act not merely as “switches” of individual pathways but also as critical “hubs” that integrate multiple oncogenic signals [116]. This network-level regulatory architecture not only explains the high heterogeneity and therapy resistance observed in melanoma but also suggests that targeting these nodal proteins may yield synergistic therapeutic effects with significant clinical potential.

However, three major challenges persist in clinical translation: intrinsic “undruggability”, context-dependent functional characteristics, and limitations of monotherapy. A primary bottleneck is the widely recognized “undruggability” of many RNFs. Most family members, such as RNF157 and c-CBL, exert their functions through transient protein–protein interactions mediated by their RING domains, which interface with E2 enzymes and substrates. These interfaces often lack deep hydrophobic pockets that are amenable to conventional small-molecule binding.

Nevertheless, this challenge has spurred the development of innovative therapeutic modalities. For instance, allosteric inhibitors—such as those targeting the TKB–LHR interface of c-CBL, can stabilize inactive conformations; “molecular glues” can be engineered to induce nonphysiological complexes with E2 enzymes or substrates, leading to functional disruption. Covalent inhibition strategies have also shown considerable promise, as exemplified by inhibitors targeting ML-IAP Lys135 or RNF114 Cys8, which achieve high selectivity by engaging key residues outside the catalytic domain. Additionally, PROTAC technology offers a breakthrough path by facilitating the degradation of RNFs themselves or repurposing them as “recruitment handles” to degrade other oncoproteins, thus bypassing the need for direct catalytic inhibition. Advances in artificial intelligence (AI)-assisted protein structure prediction and molecular dynamics simulations are accelerating the design of such innovative agents, opening new avenues to overcome the historical undruggability of this protein family.

Another major challenge is the context-dependent functionality of RNFs, which plays a polarized role in melanoma with different gene mutation types, complicates their clinical targeting, and underscores the necessity of combination strategies. Moreover, clinical treatment may achieve precise patient stratification through biomarker systems based on p53 status, driver mutations, and specific RING finger protein expression profiles. Leveraging their roles as signaling integrators, RNF-targeting agents show strong rationale for use with standard therapies: MDM2 inhibitors, Parkin agonists, or RNF43 activators may reverse MAPK inhibitor resistance; targeting MARCH proteins or c-CBL can remodel the immune microenvironment to enhance checkpoint blockade; and TRIM28 inhibitors may suppress growth without promoting invasion, potentially augmenting cell cycle or anti-angiogenic agents.

At the same time, combination therapy involving MAPK inhibitors and immune checkpoint inhibitors can produce synergistic effects, reversing drug resistance and remodeling the tumor microenvironment. As preclinical evidence accumulates, there is an urgent need for well-designed clinical trials to validate these combination regimens and translate RNF regulation into effective therapeutic strategies.

Looking ahead, multidisciplinary research integrating structural biology, computational chemistry, and precision medicine will drive RING protein-targeting strategies from concept to clinical application, providing a new generation of precision tools to tackle melanoma heterogeneity and treatment resistance. In summary, RNF serves as a key signaling hub in melanoma, driving drug development away from binding-site-based inhibition toward novel paradigms such as targeted degradation. Interdisciplinary integration is crucial for overcoming ‘undruggability’ and context-dependent functions, and is expected to reshape precision therapy for melanoma over the next decade.

Abbreviations

RING

Really interesting new gene

RNFs

RING finger E3 ubiquitin ligases

RNF

The RING finger protein

MAPK

Mitogen-activated protein kinase

PI3K

Phosphoinositide 3-kinase

PROTAC

Proteolysis-targeting chimeras

TRIM

Tripartite Motif-containing

RING-UIM E3s

Really interesting new gene-ubiquitin interacting Motif E3 ubiquitin ligases

MARCH

Membrane-associated RING-CH

PA-TM-RING E3s

Pseudoatutimmune transmembrane really interesting new gene E3 ubiquitin ligases

RBR

RING-between-RING

HECT

Homologous to E6-AP C-terminus

DNA

Deoxyribonucleic acid

UIMs

Ubiquitin-interacting motifs

ARF

ADP-ribosylation factor

CDKN2A

Cyclin-dependent kinase inhibitor 2A

TGF-β

Cyclin-dependent kinase inhibitor 2A

P53

Protein 53

MDM2

Mouse double minute 2 homolog

ERK

Extracellular signal-related kinase

CDKN2A

Cyclin-dependent kinase inhibitor 2A

ARF

ADP-ribosylation factor

MDMX

Murine double minute X

NRAS

Neuroblastoma RAS viral oncogene homolog

CD44

Cluster of differentiation 44

CTTN

Cortactin

EMT

Epithelial mesenchymal transition

WNT5A

Wnt family member 5A

ROR1

Receptor tyrosine kinase-like orphan receptor 1

LTBP2

Latent transforming growth factor beta binding protein 2

ROR2

Receptor tyrosine kinase-like orphan receptor 2

MEK

Mitogen-activated extracellular signal-regulated kinase

LTBP2

Latent transforming growth factor beta-binding protein 2

H2AK119

Histone H2A lysine

CCND2

Cyclin D2

H3K27me3

Methylation histone H2A lysine

UTX

Ubiquitously transcribed tetratricopeptide repeat on chromosome X

P300

E1A-associated protein

YAP1

Yes-associated protein 1

CXCL2

C–X–C motif chemokine ligand 2

CXCL8

Interleukin 8

PTEN

Phosphatase and Tensin homolog deleted on chromosome 10

STAT3

Signal transducer and activator of transcription 3

APC/C-CDH1

Anaphase-promoting complex/cyclosome (APC/C)-CDH1

CDK2

Cyclin-dependent kinase 2

FAK

Focal adhesion kinase

SRC

Steroid receptor coactivator

GRB2

Growth factor receptor-bound protein 2

ERK1/2

Extracellular signal-regulated kinase 1 and 2

PROTACs

Proteolysis-targeting chimeras

IAP

Inhibitor of apoptosis protein

AP-1

Activator protein 1

SMAC

Second mitochondria-derived activator of caspases

BIR2

Baculovirus IAP repeat 2

BIR3

Baculovirus IAP repeat 3

XIAP

X-linked inhibitor of apoptosis protein

cIAP1/2

Cellular inhibitor of apoptosis protein 1/2

ML-IAP

Melanoma inhibitor of apoptosis protein

ArSF

Aryl sulfonyl fluoride

TKB

Tyrosine kinase-binding

LHR

Linker helix region

CRL4CRBN

Cullin-RING ligase 4-cereblon

AKT

Ak strain transforming

PARP-1

Poly (ADP-ribose) polymerase 1

Author contributions

J.Z. and X.L. contributed to the conceptualization, formal analysis, and original draft preparation. L.L., Y.Y., S.Z., and C.G., contributed to the methodology, validation, and visualization. X.Z., H.X., and X.L. reviewed and polished the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 82574643) and the China International Medical Foundation (grant no. Z-2021-46-2101-2023).

Data availability

No data was used for the research described in the article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.