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Introduction

Malignant tumors remain the leading cause of death worldwide, driven by factors including genetic variation, dysregulated signaling pathways and microenvironmental adaptation. Cancer is expected to cause an estimated 618,120 deaths in the United States in 2025 (1). Global trends reflect similar patterns, highlighting the heavy burden of cancer deaths on all populations. Tumor occurrence and progression involve complex molecular mechanisms, including gene mutation, aberrant signaling pathway, and changes in the tumor microenvironment (TME) (2-4). Despite advances in treatment, challenges such as metastasis, recurrence and drug resistance persist, necessitating a deeper understanding of the molecular drivers of malignancy (5,6).

RNA-binding proteins (RBPs) have garnered attention as central regulators of post-transcriptional gene expression, influencing RNA stability, splicing and translation (7,8). Initially identified in Caenorhabditis elegans, human muscle excess (MEX)3A is implicated in stem cell (SC) maintenance, immune regulation and tumor progression (9,10). MEX3A contains conserved K homology (KH) and really interesting new gene (RING) domains, which are involved in RNA metabolism and protein ubiquitination, respectively (9,11). While MEX3A has been characterized predominantly as an oncogenic driver because of its role in promoting stemness, proliferation and immune evasion, emerging evidence suggests that its functional role may be context-dependent (12). In certain tumor types, such as cervical cancer, MEX3A exhibits tumor-suppressive properties by inhibiting cell migration and the epithelial-mesenchymal transition (EMT) via the AKT signaling pathway (13-15). This duality underscores the need for a nuanced understanding of the biological functions of MEX3A in distinct cancer types and developmental stages. MEX3A binds and regulates the stability and translation of specific mRNAs, and it mediates protein degradation via its E3 ubiquitin ligase activity, thereby influencing processes such as SC self-renewal, differentiation, RNA metabolism and immune responses (10,16-18). MEX3A upregulation is closely associated with the development and progression of numerous types of cancer and key pathological processes such as the maintenance of cancer SC (CSC) self-renewal, regulation of tumor cell proliferation and migration and the activation of immune evasion mechanisms (19-21). However, its cancer-specific mechanisms and clinical relevance remain underexplored. The present review summarizes the structural and functional dynamics of MEX3A, its roles in cancer and its therapeutic implications, aiming to bridge the gap between molecular insights and clinical translation.

Structure and function of MEX3A

As a crucial member of the RNA-binding protein family, MEX3A is a key post-transcriptional regulator involved in modulating diverse cellular processes. Through a systematic genetic analysis, Draper et al (10) identified the key roles of MEX3 proteins in mRNA localization and translational control. Buchet-Poyau et al (9) discovered four human homologs (MEX3A-D) that share conserved domains, including two KH domains for RNA recognition, a catalytically active RING domain and a functional nuclear export signal (NES) in the N-terminal region (Fig. 1A). The KH domains enable MEX3A to interact with mRNAs, regulating RNA stability and translation, whereas the RING domain possesses E3 ubiquitin ligase activity, mediating substrate-specific proteasomal degradation via ubiquitination (9). Notably, the NES facilitates nucleocytoplasmic shuttling, a prerequisite for the spatiotemporal regulation of RNA metabolism by MEX3A and its integration with signaling networks (9). These structural determinants establish MEX3A as a multifunctional scaffold that integrates RNA processing with protein quality control systems.

Figure 1 Structure and function of MEX3A. (A) Domain structure of the human MEX3A protein and its RNA-binding domain. The KH domain enables MEX3A to bind to target mRNAs and regulate their stability, translation or localization. Data were obtained from the UniProt database (uniprot. org/uniprotkb/A1L020/entry; accessed on 7 March 2025). (B) Predicted three-dimensional structures from AlphaFold for the MEX3A protein. The protein comprises two conserved K homology domains and a RING domain. Each KH domain adopts a topology consisting of three α-helices and three β-strands arranged in an open palm-like configuration. The C-terminal RING domain forms a compact cross-β structure stabilized by eight conserved cysteine residues that coordinate two zinc ions in a tetrahedral geometry. When binding RNA, the KH domain may form RNA-binding grooves through spatial alignment, similar to the complex structure of MEX3A and RNA, which bind specific sequences of single-stranded RNA. Data obtained from the GeneCards database (genards.org/cgi-bin/carddisp.pl?gene=MEX3A). (C) MEX3A protein inhibits autophagy in colon cancer cells by affecting the post-transcriptional decay of the PDE5A mRNA via the circMPP6 complex. (D) MEX3A can bind to RIG-I and induce its ubiquitination and proteasome-dependent degradation. RIG-I is a key pattern recognition receptor of the innate immune system that activates antitumor immune responses and inhibits tumor cell proliferation. In tissue with high MEX3A expression, RIG-I is inhibited, and tumor growth is rapid, however, in the case of low expression of MEX3A or depletion, RIG-I protein levels increase, thereby inhibiting the proliferation of tumor cells. MEX3A, Mex-3 RNA Binding Family Member A; KH, K-homology domain; RING, Really Interesting New Gene domain; PDE5A, Phosphodiesterase 5A; circMPP6, circular RNA derived from the MPP6 gene; RIG-I, retinoic acid-inducible gene I; P, phosphorylation.

Molecular structure

MEX3A contains two N-terminal KH structural domains for RNA interaction and a C-terminal RING structural domain that confers E3 ubiquitin ligase activity. The NES promotes nucleoplasmic shuttling for the spatiotemporal regulation of RNA metabolism and protein degradation (11) (Table I).

Table I Muscle excess 3A functional domains and regulatory mechanisms.

Table I

Muscle excess 3A functional domains and regulatory mechanisms.

Structural domain/feature	Structure	Molecular mechanism	Physiological/pathological effects	(Refs.)
KH structural domain	N-terminal tandem double KH structural domain containing a β-folding hydrophobic cavity	Recognition of the AU-enriched element of the LGR5 mRNA 3′UTR; recruitment of the CCR4-NOT complex regulates mRNA stability	Maintenance of intestinal stem cell self-renewal; regulation of embryonic development-associated gene expression	(11)
RING structural domain	C-terminal zinc finger structure with an E2 binding interface	Catalyzes K48-linked poly-ubiquitination chains; mediates RIG-I K813 site-specific ubiquitination	Promotes immune escape in colorectal cancer; modulation of the Wnt/β-catenin signaling pathway	(114)
P-body positioning	N-terminal hDcp1a reciprocal region; C-terminal LSm14A anchor locus	Formation of the mRNA deadenylation-decapping complex; spatial restriction regulates the translational suppression of differentiated genes such as SOX9	Maintains stem cell pluripotency; involved in the epithelial-mesenchymal transition process	(15,20)
Phosphorylation	Six conserved phosphorylation sites	CDK2 phosphorylation of S308 enhances nuclear export; AKT phosphorylation of S415 regulates RNA binding/E3 activity switching	Promotes tumor cell proliferation; responds to DNA damage stress	(15)
SUMO modification	SUMO binding motifs at the K297/K406 site	Enhances NLS activity; inhibits CRM1-mediated nuclear export	Regulates embryonic developmental timing; affects tumor metastatic potential	(10)
Nuclear plasmic shuttle motif	NES region (residues 340-350); NLS region (residues 120-135)	CRM1-dependent active transport; stress-induced intranuclear pri-miRNA binding	Maintenance of mRNA monitoring system homeostasis; regulation of microRNA biosynthesis	(45)

[i] KH, K-homology domain; AU, Adenine-U racil-rich element; LGR, Leucine-G lycine repeats; UTR, Untranslated R egion; CCR4-NOT, CCR4-NOT transcription complex; RING, ; RIG-I, Retinoic acid-inducible gene I; P, Phosphorylation; hDcp1a, human Decapping protein 1a; LSm14A, Like Sm protein 14A; SOX, S RY-box containing protein; SUMO, Small Ubiquitin-like Modifier; NLS, Nuclear Localization Signal; CRM, Chromatin Remodeling Modifier; NES, Nuclear Export Signal; pri, Primary transcript.

RNA recognition by the KH structural domain

The core function of the MEX3A protein is determined by its N-terminal tandem KH domains, which are hallmark molecular features of RNA-binding proteins (11). The KH domains recognize adenine-Uracil rich-rich RNA cis-elements through a hydrophobic cavity formed by β-sheets, with their binding affinity dynamically regulated by RNA secondary structures. At the molecular regulatory level, MEX3A binds to the 3′ untranslated region (UTR) of the Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) mRNA via its KH domains, forming ribonucleoprotein complexes that maintain mRNA stability. This mechanism serves a critical regulatory role in the self-renewal of intestinal SCs (Fig. 1B) (7,11,22).

Ubiquitination regulatory network driven by the RING domain

The C-terminal RING domain confers E3 ubiquitin ligase activity to MEX3A, which relies on the formation of complexes with specific E2 conjugating enzymes to execute its functions (11,23). This domain facilitates the transfer of ubiquitin molecules from E2 to the lysine residues of target proteins through zinc finger motif-mediated allosteric effects, initiating K48-linked polyubiquitination degradation signals. Notably, in the colorectal cancer (CRC) microenvironment, MEX3A catalyzes the ubiquitination of retinoic acid-inducible gene I (RIG-I) at the K813 residue via its RING domain, promoting its proteasomal degradation and suppressing the type I interferon signaling pathway (11,24). This discovery provides a molecular explanation for tumor immune evasion mechanisms.

Functional integration in processing-body (P-body) micro-compartments

Subcellular localization analyses have revealed that MEX3A is localized to the P-body (25), where it forms stable interactions with the human decapping protein 1a decapping enzyme and Glycine-Tryptophan protein of 182 kDa (GW182) protein through its N-terminal sequence (9). Cryogenic Electron Microscopy (Cryo-EM) structural studies showed that the C-terminal α-helix of MEX3A anchors to the P-body scaffold protein-like Sm protein 14A (LSm14A), creating a spatially confined mRNA degradation microenvironment (26,27). During SC differentiation, MEX3A coordinates mRNA deadenylation (26,27), decapping and 5′-3′ exonuclease activities within P-bodies to achieve the translational suppression of differentiation-related genes. This dynamic regulatory network provides an epitranscriptomic node for cell fate determination (28,29). Chen et al (28) studied CRC and showed that circular (circ)RNAs promote the formation of functional complexes between MEX3A and associated functional proteins, thereby regulating the Phosphodiesterase 5A mRNA and suppressing autophagy (Fig. 1C).

Dynamic regulation by post-translational modification

Mass spectrometry has identified six conserved phosphorylation sites in MEX3A (S112, S215, S308, T324, S415 and S506). Among these, CDK2-dependent phosphorylation at S308 enhances its interaction with exportin-1 (CRM1). Notably, AKT-mediated phosphorylation at S415 disrupts the RNA-binding capacity of the KH domain while simultaneously enhancing the E3 ligase activity of the RING domain. This dual regulatory mechanism may serve a key role in tumorigenesis. Additionally, Small Ubiquitin-like Modifierylation (SUMOylation) has been shown to modulate the nucleocytoplasmic shuttling efficiency of MEX3A, suggesting the existence of a multilayered regulatory network. Bufalieri et al (29) demonstrated that MEX3A binds to RIG-I and induces its ubiquitination and proteasomal degradation. RIG-I, a key pattern recognition receptor in the innate immune system, activates antitumor immune responses to inhibit tumor cell proliferation (29). However, the depletion of MEX3A leads to increased RIG-I protein levels, thereby suppressing tumor cell proliferation (Fig. 1D) (9,29).

Regulatory role of the spatiotemporal localization of MEX3A

The subcellular distribution of MEX3A is regulated by dual nuclear localization signals and the NES, with its nucleocytoplasmic shuttling dependent on CRM1-mediated active transport. In quiescent cells, MEX3A is localized primarily in cytoplasmic P-bodies, where it serves mRNA surveillance functions (9). Following DNA damage, the proportion of MEX3A in the nucleus increases, regulating Drosha processing by binding to primary miRNAs. This dynamic shift in localization may constitute a key regulatory mechanism in cell stress responses (29).

Biological functions of MEX3A

MEX3A, a conserved member of the RBP family, serves a multifaceted role in cellular regulation by integrating RNA metabolism and protein homeostasis. Its dual regulatory characteristics enable it to serve as a key molecular switch, maintaining cell homeostasis under physiological conditions while driving malignant transformation in pathological states (11). As an RBP, MEX3A exerts control over gene expression by modulating RNA stability and translation efficiency, primarily by binding to the 3′UTR of target mRNAs. This post-transcriptional regulation allows MEX3A to fine-tune the expression of genes involved in cell cycle progression, differentiation and stress responses (30). In addition to its RNA-binding ability, MEX3A exhibits intrinsic E3 ubiquitin ligase activity, which enables it to participate in protein degradation pathways (3,17). This unique combination of functions positions MEX3A as a key regulator at the interface of RNA metabolism and protein turnover.

Through its E3 ubiquitin ligase activity, MEX3A targets specific proteins for proteasomal degradation, thereby influencing cellular processes, including signal transduction, cell fate determination and stress adaptation (31). The functional network of MEX3A extends beyond individual molecular interactions, encompassing broader regulatory roles in coordinating signaling pathways key for development and disease. During embryonic development, MEX3A contributes to the precise spatiotemporal regulation of gene expression patterns necessary for proper tissue patterning and organogenesis. In adult tissue, MEX3A serves a crucial role in maintaining tissue homeostasis and facilitating regeneration by regulating SC maintenance and differentiation (32). In tumorigenesis, the ability to modulate RNA stability and translation efficiency allows MEX3A to promote the expression of oncogenic factors while suppressing tumor suppressors (33). Furthermore, its E3 ubiquitin ligase activity is co-opted to degrade tumor suppressor proteins, thereby creating a pro-tumorigenic environment. MEX3A is involved in coordinating multiple signaling pathways, including the Wnt/β-catenin, PI3K/AKT and NF-κB pathways, further underscoring its role in cancer progression (34-36).

The complexity of the biological functions of MEX3A is reflected in its ability to integrate multiple regulatory layers, from post-transcriptional control to protein degradation and signal transduction (37,38). This multifunctionality makes MEX3A a key molecular hub in both physiological and pathological contexts, with its dysregulation impacting cell behavior and tissue integrity. Understanding the balance of MEX3A functions and their context-dependent regulation is a crucial area, particularly in light of its potential as a therapeutic target in various types of disease, including cancer (11,20).

Physiological functions of MEX3A

Dynamic regulation of SCs

MEX3A plays a direct role in determining the fate of intestinal and neural SCs by regulating the mRNA stability of pluripotency genes such as LGR5 and SOX2. In the intestinal crypt microenvironment, MEX3A maintains the self-renewal capacity and regenerative potential of the SC pool by suppressing the translation of differentiation-associated transcription factors (39,40). Additionally, it is key for the self-renewal and differentiation of neural SCs, influencing the proliferation/differentiation balance of neural progenitor cells (41).

Regulation of vascular homeostasis

MEX3A also serves key roles in angiogenesis and vascular protection (42). On the one hand, it increases the stability of the VEGF-A mRNA, promoting endothelial cell migration and angiogenesis. On the other hand, it inhibits the mitochondrial apoptosis pathway by ubiquitinating the BAX protein, thereby maintaining vascular endothelial integrity. Clinical pathological analyses have shown that the loss of MEX3A expression leads to endothelial barrier dysfunction and accelerates atherosclerotic plaque formation (33-45).

Pathological mechanisms of MEX3A in cancer

Regulation of oncogenic signaling pathways

MEX3A acts as a key regulator in various types of cancer, mediating tumorigenesis and progression through multiple signaling pathways. In CRC, MEX3A activates the Wnt/β-catenin signaling pathway, inducing EMT and increasing cell migration and invasion (34) (Fig. 2). Furthermore, it promotes cell proliferation via the PI3K/AKT signaling pathway and accelerates tumor progression via the RAP1/MAPK axis (46). In breast cancer, MEX3A suppresses Dickkopf-related protein 1 expression, maintaining β-catenin signaling activity and enhancing the stemness and metastatic potential of cancer cells (47) (Table II). In ovarian cancer, MEX3A inhibits ferroptosis by degrading p53, thereby promoting tumor cell survival (48). These findings highlight the regulatory role of MEX3A in multiple signaling pathways and provide a theoretical basis for its potential as a therapeutic target. MEX3A serves as an oncogene in numerous types of cancer, driving tumor initiation, progression and metastasis via the regulation of diverse signaling pathways.

Figure 2 Role of MEX3A in tumor cell signaling pathways. MEX3A regulates multiple oncogenic signaling pathways and promotes tumor cell proliferation, invasion, migration and immune evasion. MEX3A activates the RAP1GAP/MEK/ERK pathway, leading to increased E2F3 expression and upregulation of HIF-1α, a key transcription factor involved in tumor progression. Additionally, MEX3A activates the β-catenin-KLF4 axis, further promoting EMT, invasion and migration. MEX3A modulates WWC1/LATS1/YAP1/NF-κB signaling to promote cytoskeletal rearrangements, thereby increasing cell motility. Furthermore, through the PI3K/AKT pathway, MEX3A regulates the RhoA/ROCK/LIMK pathway, further increasing cell migration and invasion. MEX3A downregulates CDKN2B, leading to the disruption of the RB/E2F complex, which accelerates cell cycle progression and proliferation. MEX3A promotes immune evasion by inducing NMD of tumor suppressor genes, such as P53, thereby inhibiting ferroptosis and promoting cancer cell survival. Additionally, MEX3A facilitates the ubiquitin-mediated degradation of RIG-1, a key pattern recognition receptor, thereby impairing innate immune responses against tumors. MEX3A, Mex-3 RNA Binding Family Member A; RAP1GAP, RAP1 GTPase Activating Protein; KLF, Kruppel-Like Factor; EMT, Epithelial-Mesenchymal Transition; WWC, WW and C2 Domain Containing; LATS, Large Tumor Suppressor Kinase; LIMK, LIM Domain Kinase; CDKN2B, Cyclin-Dependent Kinase Inhibitor 2B; RB/E2F, Retinoblastoma protein/E2F Transcription Factor; NMD, Nonsense-Mediated mRNA Decay; RIG-I, Retinoic acid-inducible gene I; miR, microRNA; ETS, E twenty-six transcription factor family; DVL, Dishevelled; IGFBP, Like Growth Factor Binding Protein; LAMA, Laminin Subunit Alpha; Ub, Ubiquitin; TIMELESS, Timeless Regulator of DNA Damage Response.

Table II Mechanisms by which MEX3A regulates oncogenic signaling.

Table II

Mechanisms by which MEX3A regulates oncogenic signaling.

Regulatory pathway	Mechanism of action	Experimental models	Functional result	(Refs.)
Wnt/β-catenin	Increase in DVL2 stability via UBR5-mediated phosphorylation promotes nuclear β-catenin accumulation	CRC PDX	Enhanced tumor stem cell properties	(33,34)
PI3K/AKT/mTOR	Binding of MEX3A to the PTEN mRNA 3′UTR reduces its translation efficiency and deregulates AKT signaling inhibition	Gastric cancer-like organ	Development of chemotherapy resistance	(35,94)
RAS/MAPK	Regulation of selective KSR1 splicing promotes MEK/ERK complex assembly	NSCLC cell lines	Increased cell proliferation	(46)
TGF-β/Smad	Forms an RNA-protein complex with Smad7 and accelerates its proteasomal degradation	Murine liver cancer	Increased EMT	(15,34)
NF-κB	Maintenance of signalosome integrity by IKKγ deubiquitination	Breast cancer tissue microarray	Inflammatory microenvironment formation	(36)

[i] DVL, Dishevelled; UBR, Ubiquitin Protein Ligase E3 Component N-Recognin; CRC, Colorectal Cancer; PDX, Patient-Derived Xenograft; MEX3A, Mex-3 RNA Binding Family Member A; UTR, Untranslated Region; KSR1, Kinase Suppressor of Ras 1; NSCLC, non-small cell lung cancer.

Tumor immune evasion

Through its E3 ubiquitin ligase activity, MEX3A regulates the ubiquitination and degradation of immunomodulatory molecules, suppressing immune surveillance and promoting tumor immune escape (17,20,29). In CRC, high MEX3A expression increases tumor cell proliferation and migration via the RAP1/MAPK signaling pathway (46). The role of MEX3A in other tumor types warrants further investigation.

MEX3A upregulation is associated with therapeutic resistance in multiple types of malignancy, including breast cancer and CRC. Mechanistically, MEX3A promotes tumor cell self-renewal by modulating SC-associated gene networks, which contributes to enhanced chemoresistance (32,49). Moreover, emerging evidence suggests that the MEX3A-mediated regulation of glycolytic metabolism may support tumor cell survival in response to chemotherapeutic stress (50).

MEX3A has emerged as a key regulator of CSC maintenance that stabilizes and post-transcriptionally controls the expression of stemness markers such as LGR5 (51), thereby sustaining the self-renewal capacity of CSCs in CRC and other types of cancer (52). This function not only drives tumor growth but may contribute to disease relapse following therapy.

Tumor-specific mechanisms of MEX3A

MEX3A serves key roles in regulating RNA stability, translation, and degradation through its dual functions as both an RBP and an E3 ubiquitin ligase (11). The ubiquitination activity mediated by its RING domain enables MEX3A to mediate the degradation of target proteins, thereby influencing biological processes such as cell cycle regulation, proliferation and metastasis (29). Emerging evidence suggests that MEX3A promotes tumor initiation and progression in multiple cancer types, including CRC, breast cancer, hepatocellular carcinoma (HCC) and glioblastoma (53). However, its functional roles in less studied malignancies, such as pancreatic ductal adenocarcinoma, cervical cancer and nasopharyngeal carcinoma, are increasingly recognized (54,55). Previous findings further support a role for MEX3A in enhancing tumorigenesis and disease progression, especially in colorectal, breast, and liver cancers, where it modulates key cellular processes such as proliferation, apoptosis, and chemoresistance (21,56) (Table III).

Table III Tumor-specific mechanisms of MEX3A.

Table III

Tumor-specific mechanisms of MEX3A.

Tumor type	Mechanisms of MEX3A	Signaling pathways	Clinical value	(Refs.)
Colorectal cancer	High expression of MEX3A is associated with the tumor size, TNM stage, lymph node metastasis and a poor prognosis. It promotes tumor proliferation, invasion and metastasis by regulating Wnt/β-catenin, PI3K/AKT, MEK/ERK and other signaling pathways. It is associated with chemotherapy resistance and degrades the PDE5A mRNA via the circMPP6 phase separation complex, inducing autophagy-mediated chemotherapy resistance	Wnt/β-catenin, PI3K/AKT, MEK/ERK	MEX3A is an independent prognostic factor and potential a therapeutic target	(24,25,46, 49,50)
Hepatocellular carcinoma	Hypomethylation of the MEX3A promoter leads to the upregulation of its mRNA, which is associated with vascular invasion and sorafenib resistance. It promotes cancer stem cell expansion and drug resistance by inhibiting the Hippo signaling pathway	Hippo	MEX3A is a poor prognostic marker and may be a therapeutic target	(68,81, 127)
Pancreatic ductal adenocarcinoma	MEX3A binds to the CDK6 mRNA through the m6A recognition element, prolongs its half-life, drives the G1/S phase transition in the cell cycle and induces gemcitabine resistance. It regulates signaling pathways such as PI3K/AKT, CDK6 and MAPK9, promotes tumor proliferation and inhibits apoptosis	PI3K/AKT, CDK6, MAPK9	High expression of MEX3A is associated with a poor prognosis, and may be a therapeutic target	(21,74)
Esophageal squamous cell carcinoma	High expression of MEX3A is associated with an advanced stage, lymph node metastasis and poor prognosis. It promotes tumor cell proliferation, migration and anti-apoptosis by upregulating CDK6 expression	CDK6	MEX3A may serve as a biomarker and therapeutic target	(80)
Gastric cancer	High expression of MEX3A is associated with cell proliferation, migration and malignant transformation. Knockdown of MEX3A inhibits tumor cell proliferation and migration and induces apoptosis	PI3K/AKT	MEX3A may be a therapeutic target	(82)
Triple-negative breast cancer	MEX3A promotes tumor proliferation, migration and invasion by activating the PI3K/AKT, Wnt/β-catenin and RhoA/ROCK1/LIMK1 signaling pathways. It activates the PI3K/AKT pathway by binding the IGFBP4 and PIK3CA mRNA and increasing AKT phosphorylation	PI3K/AKT, Wnt/β-catenin, RhoA/ROCK1/ LIMK1	MEX3A is a marker of a poor prognosis for and may be a therapeutic target	(87)
Ovarian cancer	MEX3A mediates p53 ubiquitination and degradation through the RING domain, inhibits ferroptosis, promotes tumor cell proliferation and migration through the PI3K/AKT signaling pathway and regulates the tumor micro-environment.	PI3K/AKT	High expression of MEX3A is associated with a poor prognosis and may become a therapeutic target	(20,48)
Cervical cancer	MEX3A serves as a tumor suppressor in HPV-negative cervical cancer, inhibiting tumor cell proliferation, migration and invasion by inhibiting the AKT signaling pathway and EMT. The overexpression of MEX3A inhibits tumor growth, while its knockdown enhances tumor malignant behavior	AKT	MEX3A has dual roles in and may serve as a therapeutic target	(15,96,98)
Bladder cancer	MEX3A promotes proliferation and inhibits apoptosis in non-muscle-invasive bladder cancer cells. Following RNA interference-mediated silencing of MEX3A, tumor cell proliferation is inhibited and apoptosis is increased	MAPK/ERK	MEX3A may be a therapeutic target	(56)
Lung cancer	MEX3A enhances tumor cell migration, invasion and EMT via the PI3K/AKT signaling pathway. It binds LAMA2 mRNA, decreases its stability and activates the PI3K-AKT pathway. The circGRAMD1B/miR-4428/SOX4 axis activates the PI3K/AKT signaling pathway and increases MEX3A expression	PI3K/AKT, LAMA2	High expression of MEX3A is associated with a poor prognosis for NSCLC and may become a therapeutic target	(101-103)
Nasopharyngeal carcinoma	MEX3A activates the NF-κB signaling pathway through the miR-3163/SCIN axis, promoting tumor cell proliferation, migration and invasion. MEX3A depletion inhibits tumor growth and promotes tumor cell apoptosis	NF-κB	MEX3A may be a therapeutic target	(34,128)
Glioblastoma	MEX3A exacerbates malignant tumor progression by targeting CCL2. It binds RIG-I, promotes its ubiquitination and degradation and inhibits the anti-tumor immune response. During temozolomide treatment, MEX3A degrades the MSH2 mRNA, decreases DNA repair and enhances drug resistance	CCL2, RIG-I, MSH2	High expression of MEX3A is associated with a poor prognosis and drug resistance and may be a therapeutic target	(28,108)
Thyroid cancer	MEX3A promotes tumor cell proliferation and migration by interacting with CREB1. MEX3A depletion inhibits tumor growth and induces apoptosis in cancer cells	CREB1	High expression of MEX3A is associated with a poor prognosis and may be a therapeutic target	(35,109)

[i] MEX3A, Mex-3 RNA Binding Family Member A; TNM, Tumor-Node-Metastasis; PDE5A, Phosphodiesterase 5A; circMPP, Circular Motile Protein Particle; LIMK, LIM Domain Kinase; IGFBP4, Insulin-like Growth Factor Binding Protein 4; RING, Really Interesting New Gene; HPV, Human Papillomavirus; EMT, Epithelial-Mesenchymal Transition; LAMA, Laminin Alpha; circGRAMD1B, Circular GRAMD1B; miR, microRNA; NSCLC, Non-Small Cell Lung Cancer; SCIN, Scinderin; RIG-I, Retinoic acid-inducible gene I; MSH2.

Gastrointestinal tumors

CRC

CRC is among the leading causes of cancer-associated mortality worldwide. According to the World Health Organization Global Cancer Observatory, CRC accounted for approximately 940,000 deaths in 2020, making it the second most common cause of cancer-related death globally. (57-59). MEX3A has been consistently reported to be upregulated in CRC tissues and is positively associated with the tumor size (60), TNM stage and lymph node metastasis (46). Mechanistically, MEX3A promotes CRC progression by upregulating CDK2 and increasing cell proliferation (34,61,62). Additionally, it activates the Wnt/β-catenin signaling pathway by inhibiting KLF4 expression, facilitating EMT and tumor invasion (63). Recent studies have highlighted the role of MEX3A in glycolysis-driven tumor metabolism (64,65), where it supports energy production for rapid tumor growth (48). Notably, single-cell sequencing analyses have revealed that MEX3A+ cells exhibit drug-tolerant persister phenotypes, contributing to chemoresistance during oxaliplatin treatment (49,66).

HCC

In HCC, hypomethylation of the MEX3A promoter leads to the upregulation of the MEX3A mRNA, which is associated with vascular invasion and sorafenib resistance (67-70). Yang et al (71) identified the MEX3A methylation status as a potential diagnostic marker for HCC. Fang et al (72) observed that MEX3A promotes HCC cell proliferation and migration and mediates drug resistance by binding the 3′UTR of the WW and C2 domain-containing protein 1 mRNA, inhibiting the Hippo pathway and increasing YAP nuclear translocation, thereby expanding the number of CSCs.

Pancreatic ductal adenocarcinoma (PDAC)

PDAC is a highly aggressive malignancy with a 5-year overall survival rate of ~10% in the United States between 2010 and 2020, according to data from the Surveillance, Epidemiology, and End Results (SEER) Program. The majority of cases are diagnosed at advanced stages, with less than 20% of patients presenting with resectable disease. (73). In PDAC, MEX3A binds the CDK6 mRNA via an m6A recognition element (AGACT motif), prolonging its half-life, driving the G1/S phase transition and inducing gemcitabine resistance (21). BALB/c female nude mice studies have shown that short hairpin MEX3A reduces the tumor volume by 62% and enhances gemcitabine sensitivity (74,75).

Esophageal squamous cell carcinoma (ESCC)

ESCC is a major subtype of esophageal cancer, particularly prevalent in regions such as East Asia, Eastern Africa and parts of South America. Studies have shown that MEX3A is upregulated in ESCC tissues compared with normal esophageal epithelium (76,77). High expression levels of MEX3A are significantly correlated with advanced tumor stages (III-IV), lymph node metastasis, and reduced overall survival, suggesting its potential role as a prognostic biomarker in ESCC. (78,79). It promotes ESCC progression by upregulating CDK6, thereby inducing cell cycle progression and antiapoptotic activity (80). MEX3A knockdown significantly inhibits tumor growth and induces apoptosis, suggesting its potential as a therapeutic target in this aggressive malignancy (81).

Gastric cancer (GC)

GC is a highly aggressive malignancy with a 5-year survival rate below 30% in many regions, indicating poor patient prognosis (59). MEX3A is upregulated in GC tissues and associated with cell proliferation, migration and malignant transformation (82). Low MEX3A expression inhibits GC cell proliferation, induces cell cycle arrest and apoptosis and may reduce migration and invasion (80). As a potential oncogene, MEX3A serve a critical role in the initiation and progression of GC.

Breast and gynecological tumors

Triple-negative breast cancer (TNBC)

TNBC is one of the most common malignancies in female patients, accounting for 10-20% of all breast cancers globally (83). In TNBC, MEX3A activates the PI3K/AKT pathway through a dual mechanism. MEX3A binds to the Insulin-like Growth Factor Binding Protein 4 mRNA, preventing its degradation and increasing Insulin-like Growth Factor 1 (IGF-1) bioavailability (84). On the other hand, MEX3A directly binds the PIK3CA mRNA, increasing its translation efficiency. This dual action results in a 3.1-fold increase in AKT phosphorylation, promoting the EMT (35,85-89).

Ovarian cancer (OC)

OC is a common malignancy of the female reproductive system, with approximately 313,000 new cases and 207,000 deaths reported globally in 2020. It is frequently diagnosed at advanced stages due to non-specific early symptoms, contributing to its high mortality rate, particularly in high-income countries where incidence is elevated. (90). MEX3A is highly expressed in OC tissues (91). Studies have revealed that MEX3A mediates p53 ubiquitination and degradation via its RING domain, leading to upregulated SLC7A11 expression and increased glutathione levels, thereby inhibiting ferroptosis (92,93). Additionally, MEX3A activates the PI3K/AKT signaling pathway, promoting OC cell proliferation and migration and modulating the TME (94). MEX3A also regulates the alternative splicing of the TIMELESS circadian clock regulator (TIMELESS) gene, activating the nonsense-mediated mRNA decay pathway and further enhancing tumor invasiveness (39).

Cervical cancer

Cervical cancer remains a prevalent malignancy among women globally, with an estimated 604,000 new cases diagnosed worldwide in 2020, according to the World Health Organization. Notably, the incidence has been rising among younger women, particularly in low- and middle-income countries such as sub-Saharan Africa and parts of Asia, where limited access to screening and HPV vaccination contributes to this trend. (95-97). MEX3A may serve as a biomarker for cervical cancer (98). Although MEX3A is generally upregulated and promotes tumorigenesis in most types of cancer, Xu et al found that MEX3A exerts tumor-suppressive effects on cervical cancer and overexpression of MEX3A inhibits cervical cancer cell proliferation, migration and invasion by mediating the EMT process via the AKT signaling pathway (15). Conversely, MEX3A downregulation activates the AKT pathway, enhancing the malignancy of cervical cancer cells. These findings suggest a dual role for MEX3A in cervical cancer, highlighting its potential as a therapeutic target.

The contrasting functions of MEX3A between tumor types suggest a complex interplay between intrinsic cellular factors and the TME. Unlike its pro-tumorigenic role in other types of malignancy, MEX3A acts as a tumor suppressor in cervical cancer by inhibiting the AKT signaling pathway and suppressing the EMT (15). This functional dichotomy may arise from differences in upstream regulatory signals, the availability of interacting partners or epigenetic modifications unique to cervical cancer cells (99,100). Moreover, the presence of human papillomavirus infection, a notable driver of cervical carcinogenesis, may modulate MEX3A activity through viral protein interactions or immune-associated pathways. Understanding these tissue-specific nuances is key for accurately defining the role of MEX3A in cancer biology and guiding its application as a biomarker or therapeutic target.

Respiratory system tumors

Lung cancer

According to the World Health Organization, lung cancer was the leading cause of cancer-associated deaths globally in 2024, (67,101,102) with an estimated 1.80 million deaths (95% uncertainty interval 1.73-1.87 million), and the incidence remains high in 2024 (67,101,102). MEX3A is upregulated in lung adenocarcinoma and is closely associated with advanced tumor stage, lymph node metastasis, and a poor prognosis, particularly in cohorts from East Asia and North America (94).

High MEX3A expression promotes malignant features, particularly by increasing cell migration, invasion and the EMT through the PI3K/AKT signaling pathway (94). RNA immunoprecipitation assays showed that MEX3A directly binds the 3′UTR of the laminin subunit α2 mRNA, accelerating its degradation by recruiting the carbon catabolite Repression 4-Negative on TATA deadenylase complex (94,103). The GRAM Domain Containing 1B (circGRAMD1B)-4428/SOX4 axis acts as an upstream amplifier of MEX3A expression. circGRAMD1B contains 12 conserved miR-4428 binding sites and serves as a competitive endogenous RNA (ceRNA) to sequester this tumor-suppressive miRNA and alleviate its suppression of SOX4 transcription (31,104).

Nasopharyngeal carcinoma (NPC)

MEX3A is significantly upregulated in NPC, and its overexpression correlates with poorer clinical outcomes (36). MEX3A depletion inhibits NPC cell proliferation, migration and invasion while promoting apoptosis and suppressing tumor growth. MEX3A activates the NF-κB signaling pathway via the miR-3163/Scinderin axis to drive NPC malignancy, suggesting its potential as a therapeutic target (36).

Other tumors

Glioblastoma

Glioblastoma is one of the most aggressive types of brain malignancy and efficacy of treatment is limited (105,106). On the one hand, MEX3A enhances malignant transformation via CCL2-mediated signaling cascades (107); on the other hand, it suppresses antitumor immunity by promoting RIG-I ubiquitination and proteasomal degradation (30). MEX3A drives glioma initiation and progression by regulating processes such as cell proliferation, apoptosis and migration. Specifically, MEX3A exacerbates tumor progression by targeting monocyte chemoattractant protein-1 (CCL2) (107). Additionally, MEX3A confers chemoresistance by destabilizing the MutS Homolog 2 mRNA, thereby impairing DNA repair mechanisms in temozolomide-treated cells (108). MEX3A knockdown increases RIG-I protein levels, inhibiting glioma cell proliferation (108). These multifaceted oncogenic activities position MEX3A as a promising therapeutic target, as its inhibition may counteract glioblastoma growth, immune evasion and treatment resistance.

Thyroid cancer

Thyroid cancer is one of the most common types of endocrine malignancy, accounting for ~90% of all endocrine cancers worldwide. According to the World Cancer Observatory and GLOBOCAN 2020, it ranks as the 10th most commonly diagnosed cancer globally, with >586,000 new cases reported in 2020. In the United States, the American Cancer Society estimated approximately 43,800 new cases in 2023, with a 5-year relative survival rate exceeding 98% when diagnosed at an early stage. (109,110). Studies indicate that high MEX3A expression in thyroid cancer is significantly associated with a poor prognosis and may promote tumor progression by regulating RNA stability and post-transcriptional processes (111,112). MEX3A interacts with cAMP response element-binding protein 1 (CREB1) to increase thyroid cancer cell proliferation and migration (37). Depletion of MEX3A significantly suppresses tumor growth and induces cancer cell apoptosis (19), highlighting the key role of the MEX3A-CREB1 axis in thyroid cancer development. MEX3A may serve as a novel prognostic biomarker and therapeutic target in thyroid cancer.

MEX3A orchestrates tumor progression through interactions with RNA and protein substrates, leveraging its dual functions as an RNA-binding protein and E3 ubiquitin ligase. These interactions modulate key oncogenic pathways by stabilizing pro-tumorigenic mRNAs or degrading tumor-suppressive factors (8,111). For example, MEX3A binds m6A-modified transcripts to prolong their stability, facilitates the ubiquitination-mediated proteasomal degradation of key regulators such as p53 and RIG-I and engages in ceRNA networks to amplify oncogenic signaling (110). Validated molecular targets of MEX3A across cancer types and their roles in driving proliferation, metastasis and therapeutic resistance are presented in Table IV. These findings underscore the therapeutic potential of disrupting MEX3A interactions to counteract tumor progression and improve clinical outcomes.

Table IV Interactions of muscle excess 3A with target genes and proteins.

Table IV

Interactions of muscle excess 3A with target genes and proteins.

Target	Function	Tumor types	(Refs.)
RIG-I	Suppression of the immune response and promotion of tumor immune escape	CRC, glioma	(30)
LGR5	Maintaining stem cell stability and regulating stem cell properties	CRC	(51,118)
KLF4	Inhibition of terminal differentiation regulators activates the Wnt/β-catenin pathway		(63)
CDK2	Induces cell cycle arrest and inhibits cell proliferation		(34,61,62)
RAP1GAP	Activates signaling pathways to promote tumor cell invasion and proliferation		(46)
PDE5A	Regulation of mRNA degradation increases the invasiveness of CRC cells		(28,29)
SMYD2	Activation of MEX3A expression promotes CRC cell proliferation and migration		(62)
CDK6	Stabilizes cyclin mRNA and promotes tumor proliferation	Pancreatic and esophageal cancer	(21,80)
TIMELESS	Promotes selective mRNA splicing to increase proliferation and invasion	Ovarian cancer	(39)
DVL3	Activation of the Wnt/β-catenin signaling pathway enhances the epithelial-mesenchymal transition process	Endometrial cancer	(33)
SOX4	Activates transcription to promote malignant behaviors	Lung cancer	(31,107)
LAMA2	Modulates signaling pathways to increase the metastasis of lung cancer		(94)
CREB1	Promotes cell proliferation and migration	Thyroid cancer	(35)
BTG2	Increases oncogene expression and inhibits proliferation	Clear cell renal cell carcinoma	(37)
CCL2	Promotes glioma progression	Glioma	(107)
MSH2	Decreases the DNA repair capacity and increases drug resistance		(28)
IGFBP4	Activates the PI3K/AKT signaling pathway to promote proliferation and migration	Breast cancer	(84)
PIK3CA	Activates the PI3K/AKT signaling pathway to promote tumor cell proliferation, migration and survival		(85-89)
SCIN	Activation of the NF-κB signaling pathway promotes nasopharyngeal carcinoma cell proliferation and migration		(36)

[i] RIG-I, Retinoic acid-inducible gene I; CRC, Colorectal cancer; LGR, Leucine-rich repeat-containing G-protein coupled receptor; KLF, Kruppel-like factor; RAP1GAP, RAP1 GTPase activating protein; PDE, Phosphodiesterase; SMYD, SET and MYND domain-containing protein; TIMELESS, Timeless Circadian Regulator; DVL, Dishevelled segment polarity protein; LAMA, Laminin subunit alpha; BTG, B-cell translocation gene; MSH, MutS homolog; IGFBP4, Insulin-like growth factor binding protein 4; SCIN, Scinderin.

Role of MEX3A in the TME

Cell heterogeneity and dynamic molecular networks within the TME drive tumor progression and therapeutic resistance. MEX3A is associated with immune cell infiltration in tumors (20). As a key regulatory node in the TME, MEX3A performs multiple functions in malignant transformation by coordinating processes such as immune suppression, angiogenesis, stromal remodeling and metabolic adaptation (Fig. 3).

Figure 3 MEX3A modulates the tumor immune microenvironment through cellular and molecular regulation. MEX3A is associated with immune cell infiltration in tumors, negatively associated with dendritic cell infiltration levels and positively associated with T cells and neutrophils. High MEX3A expression enhances tumor immune escape. MEX3A expression is associated with PD-1 expression. High MEX3A expression promotes the immunosuppressive microenvironment. Inhibiting proinflammatory cytokines and enhancing immunosuppressive factors to create an immunosuppressive microenvironment may enhance immune escape by regulating the Wnt/β-catenin pathway. MEX3A, Mex-3 RNA Binding Family Member A; DVL, Dishevelled; TCF, T Cell Factor.

MEX3A and tumor immune evasion mechanisms

MEX3A promotes immune evasion by binding RIG-I and inducing its ubiquitination and proteasome-dependent degradation (29). RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune responses, is typically downregulated, or RIG-I signaling is disrupted in tumor cells to evade immune surveillance. The activation of RIG-I enhances antitumor immunity, whereas the genetic depletion of MEX3A increases RIG-I protein levels and suppresses tumor cell proliferation (113,114). Xie et al (24) reported that MEX3A facilitates cancer progression by triggering the E3 ubiquitin ligase-mediated degradation of RIG-I. IGF-1Rβ phosphorylates the interdomain region at Tyr64 and Tyr250, opening the really interesting new gene domain of MEX3A and activating β-Arrestin 2 (βarr2). These findings highlight MEX3A and RIG-I as promising therapeutic targets in cancer.

MEX3A and its interactions with TME cells

MEX3A is associated with tumor immunology, and its amplification is associated with immune-related genes, particularly late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (LAMTOR2), which influences macrophage and dendritic cell functions, thereby modulating cancer immunity (115). Frequent alterations in LAMTOR2 underscore the importance of MEX3A in immune cell homeostasis, providing novel insights into its role in cancer immunology. Lin et al found that MEX3A overexpression may regulate the recruitment and function of immune cells within the TME (116). As an RNA-binding protein, MEX3A may modulate immune-related gene expression, impacting immune cell functionality and the immune status of the TME (117). It may also indirectly influence immune cell activity by regulating RNA stability, translation or splicing. Yang et al (118) observed that while MEX3A gene sequences and copy numbers are stable in patients with non-small cell lung cancer (NSCLC) (118), its overexpression is significantly associated with shorter overall survival of patients with lung adenocarcinoma. High MEX3A expression is associated with immune cell infiltration, suggesting that its role in shaping the immune TME influences NSCLC progression and prognosis.

MEX3A as a clinical biomarker and therapeutic target

MEX3A is a prognostic biomarker in cancer

The tumorspecific overexpression of MEX3A and its association with clinical outcomes position it as a potential diagnostic and prognostic biomarker. Current clinical detection techniques for MEX3A primarily include immunohistochemistry, reverse transcription-quantitative PCR, next-generation sequencing panels and liquid biopsy, each with distinct applications and limitations (Table V). Numerous studies have shown that the aberrant upregulation of MEX3A in CRC (58,67), breast cancer and HCC is significantly associated with an advanced tumor stage, increased risk of metastasis and decreased overall survival. The link between MEX3A overexpression and malignant progression has been validated in numerous types of cancer. For example, Ji et al (119) reported that MEX3A is a highly sensitive and specific marker for all glioma subtypes, with its expression associated with an older age, higher tumor grade and elevated EGFR and Ki67 levels. Genetic depletion of MEX3A suppresses the growth of primary glioblastoma both in vitro and in vivo. Xu et al (66) demonstrated that MEX3A marks a subset of LGR5+ intestinal SCs that are resistant to chemotherapy and γ-radiation, and its expression levels are associated with EMT phenotypes. Additionally, Yang et al (118) revealed that MEX3A mRNA levels are associated with the survival rates and clinical features of patients with HCC. MEX3A likely promotes cancer cell proliferation, migration, and stemness by suppressing CDX2 expression, thereby driving liver cancer progression. These findings suggest that MEX3A may serve as a biomarker for predicting treatment response, prognosis and resistance in patients with cancer (118).

Table V Limitations of MEX3AD detection methods.

Table V

Limitations of MEX3AD detection methods.

Technique	Principle	Applications	Limitations
Immunohistochemistry	Localization and semi-quantitative analysis of MEX3A protein levels in tissue	Postoperative pathological staging, prognostic assessment	Dependence on antibody specificity, difficult to monitor dynamically
Reverse transcription-quantitative PCR	Quantification of the MEX3A mRNA expression	Rapid screening of peripheral blood or tissue samples	Need for standardized internal references, tissue heterogeneity affects the results
Next-generation sequencing panel	Multigene co-testing (with MEX3A mutation or abnormal expression)	Accurate disease subtyping to support companion diagnostic strategies	High cost, complex data analysis and specialized interpretation required
Liquid biopsy	Detection of nucleic acid or protein markers of MEX3A in ctDNA or exosomes	Non-invasive, dynamic monitoring, efficacy assessment and relapse warning	Sensitivity is limited by the tumor load and sample quality

[i] MEX3A, Mex-3 RNA-binding Family Member A; ct, circulating tumor.

Potential of MEX3A as a therapeutic target in cancer

MEX3A serves a critical role in tumorigenesis and cancer progression. It is highly expressed in numerous types of cancer, including CRC, glioma and lung cancer (31,34,107). MEX3A promotes tumor proliferation and metastasis by binding and degrading the mRNAs of target genes such as RIG-I and p21, thereby activating oncogenic signaling pathways such as the Wnt/β-catenin pathway (28,33,113). Additionally, MEX3A increases the viability of CSCs by regulating the expression of SC-associated genes such as LGR5 and OCT4, increasing the risks of tumor recurrence and metastasis. Furthermore, MEX3A reduces the sensitivity of tumor cells to chemotherapeutic agents by suppressing the expression of apoptosis-associated proteins, including BAX (15,47). In breast cancer, MEX3A attenuates the efficacy of targeted therapies by modulating feedback mechanisms in the EGFR or HER2 signaling pathways (35,47,120). MEX3A also contributes to the formation of an immunosuppressive TME by degrading the mRNAs of immune-related genes, decreasing tumor antigen presentation and inhibiting T cell infiltration. Combining MEX3A inhibition with chemotherapy or immunotherapy may enhance therapeutic efficacy (2,3,14,113).

Clinical translation prospects and future directions

The present review summarized the key regulatory roles of MEX3A in various cancers, highlighting its potential as a therapeutic target. As a key member of the RBP family, MEX3A serves pivotal roles in post-transcriptional regulation, RNA metabolism and protein ubiquitination (37,121,122). By modulating RNA metabolism and protein degradation, MEX3A influences multiple aspects of tumorigenesis, progression and therapy resistance, as its upregulation is associated with poor clinical outcomes, further underscoring its clinical relevance.

Clinical translation and applications

In-depth studies on the roles of MEX3A in tumorigenesis and progression have laid the foundation for its clinical application (123,124). MEX3A exhibits notable oncogenic activity in various cancers through its KH domain-mediated RNA-binding activity and RING domain-dependent E3 ubiquitin ligase function (10,48,50). Numerous studies have shown that MEX3A is highly expressed in CRC (31,34), breast cancer and HCC and its expression is negatively associated with the patient prognosis. These findings support MEX3A as both a prognostic biomarker and a therapeutic target (47,53). As a prognostic biomarker, integrating MEX3A expression into existing tumor classification systems can increase the accuracy of outcome predictions. For example, in CRC, Wang et al (66) found that combining MEX3A expression with the TNM stage and the KRAS mutation status significantly improves the accuracy of the recurrence risk prediction. Analyzing MEX3A expression may identify high-risk patients, enabling more aggressive treatment and follow-up strategies. Small-molecule inhibitors targeting the functional domains of MEX3A have shown promise in preclinical studies (82,91). The downregulation of MEX3A suppresses tumor growth and metastasis in vitro. However, designing targeted therapies for MEX3A is challenging because of its structural complexity. Future strategies may include nanoparticle-based delivery systems to target tumor cells or MEX3A-specific monoclonal antibodies to inhibit its activity and suppress tumor progression (83,103). Notably, the dual functions of MEX3A, which are mediated by its KH domain (RNA-binding) and RING domain (E3 ubiquitin ligase), provide multiple opportunities for targeted intervention.

Targeting the KH domain

As the primary RNA-binding module, the KH domain represents a promising therapeutic target. This domain recognizes AU-rich elements in the 3′UTR of oncogenic mRNAs, such as LGR5, CDK6 and SOX4, thereby stabilizing their expression and promoting tumor growth. Small molecules capable of disrupting KH domain-RNA interactions or antisense oligonucleotides that mask MEX3A-binding sites on target mRNAs are under investigation (35,80,107). Such approaches may selectively degrade oncogenic transcripts without affecting global RNA metabolism.

Targeting the RING domain

The RING domain serves as the catalytic core of MEX3A for E3 ubiquitin ligase activity, enabling it to mediate the proteasomal degradation of tumor suppressors such as RIG-I and p53 (24,29). Inhibition of this domain may restore innate immune signaling and induce apoptosis in tumor cells. Potential strategies include the use of RING-binding peptides, dominant-negative MEX3A mutants and small-molecule inhibitors designed to interfere with RING-E2 conjugating enzyme interactions. Structural modeling and high-throughput screening are being used to identify compounds that selectively bind and inactivate the RING domain.

Inhibiting nucleocytoplasmic shuttling via the NES

MEX3A contains a conserved NES that facilitates its translocation between the nucleus and cytoplasm, a process essential for its localization to P-bodies and post-transcriptional regulatory functions. Selective inhibitors of nuclear export, such as selinexor, have shown promise in preclinical models because they trap MEX3A in the nucleus and prevent its interaction with cytoplasmic targets. This strategy may enhance conventional therapies by enhancing immune activation and decreasing tumor cell plasticity.

Collectively, these domain-specific targeting approaches offer a multipronged strategy for inhibiting MEX3A function in cancer. Further studies leveraging structural biology, chemical screening and tumor-specific delivery systems are key for translating these concepts into clinical application.

Future research and challenges

Despite its potential, the clinical application of MEX3A faces challenges. First, translating the experimental findings into clinical practice requires substantial effort. Additionally, the complexity of the regulatory network of MEX3A and its tissue-specific functions necessitate further investigation, particularly into its differential regulation in various TMEs. Previous studies have shown that MEX3A modulates key signaling pathways, such as the Wnt/β-catenin, PI3K/AKT, Hippo, and NF-κB pathways (34-36,62), with a focus on its roles in tumor cell proliferation and migration. However, MEX3A may serve dual biological functions, depending on the TME (4,14,18), genetic background and post-translational modifications. For example, in cervical cancer, MEX3A inhibits tumor progression by suppressing the AKT-mediated EMT (15). Furthermore, the interaction of MEX3A with different RNA targets and binding partners may alter its function by shifting it from an oncogene to a tumor suppressor. These findings suggest that MEX3A is not a universal oncogene but rather a context-dependent regulator of tumorigenesis. Understanding the molecular switches that govern this functional plasticity is key for harnessing MEX3A as a therapeutic target.

As a multifunctional protein, MEX3A serves essential roles in normal tissues, potentially leading to off-target effects and toxicity of targeted therapies (58,101,125). Developing tumor-specific delivery systems or leveraging TME features for targeted inhibitor release are key for addressing this issue.

Future studies should leverage advanced multi-omics technologies, including single-cell sequencing (126), proteomics and spatial transcriptomics, to systematically identify the regulatory networks of MEX3A across various cancer types and stages. A focus should be placed on its role in tumor heterogeneity. For example, single-cell RNA sequencing has revealed the critical involvement of MEX3A in maintaining CSCs, providing novel insight for the development of targeted therapies (25). These approaches may elucidate the precise mechanisms by which MEX3A contributes to tumor progression and therapeutic resistance.

Development of high-specificity inhibitors targeting the functional domains of MEX3A is a promising therapeutic strategy (29). This process includes the design of small molecules, antibody-drug conjugates and RNA interference-based therapies (127,128). Preclinical evaluations of these inhibitors in tumor models and humanized animal models are key for assessing their antitumor efficacy and safety profiles. Such efforts may lead to the identification of potent therapeutic agents capable of selectively inhibiting MEX3A activity in cancer cells.

Prospective clinical studies are needed to establish and validate MEX3A expression as a predictive biomarker for personalized treatment decisions. By integrating MEX3A expression into existing diagnostic frameworks, clinicians can better stratify patients and tailor therapeutic strategies. For example, MEX3A has potential as a molecular marker for selecting patients to receive immunotherapy, offering a novel tool for precision oncology (103).

Exploring the combined effects of MEX3A inhibition with conventional therapies such as radiotherapy, chemotherapy, immunotherapy and targeted therapies is critical. These combination strategies aim to optimize treatment efficacy while minimizing adverse effects. For example, the inhibition of MEX3A, when combined with established therapeutic approaches, could represent a novel strategy for managing refractory breast cancer, thereby addressing critical gaps in current clinical practice. Finally, investigating the role of MEX3A in circulating tumor cells and CSCs is essential for developing novel strategies to combat tumor metastasis and recurrence (69). Understanding how MEX3A contributes to the survival and propagation of these cell populations may reveal new therapeutic targets for preventing metastasis and improving long-term patient outcomes.

In conclusion, the role of MEX3A in tumor biology, coupled with advancements in drug development, position MEX3A as a promising target for precision cancer therapy. However, MEX3A exhibits a functional duality, acting as both an oncogene and a tumor suppressor, depending on the cell context, tumor type and disease stage. This dual functionality necessitates a more refined approach to targeting MEX3A in clinical settings, with consideration of its molecular interactions and regulatory networks. Future research should identify the biomarkers and molecular signatures that define the functional state of MEX3A, enabling the development of personalized therapeutic strategies tailored to individual tumor profiles. These efforts may lead to more effective and personalized treatment options for patients with cancer (108,110). However, achieving these goals requires multidisciplinary collaboration to bridge the gap between basic research and clinical application and realize the full therapeutic potential of targeting MEX3A, ultimately improving patient care and outcomes.

Availability of data and materials

Not applicable.

Authors' contributions

LLT and LZ conceived the study. SY, XL, YW, QL, JL,GW, JA, HJ, JZ and BT revised the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81960507, 82073087 and 82160112), the Science and Technology Bureau fund of Zunyi City [grant no. ZUN SHI KE HE HZ ZI (2019)93-Hao], the Science and Technology Plan Project of Guizhou Province [grant nos. QIAN KE HE JI CHU-ZK(2021)YI BAN451 and QIAN KE HE LH ZI(2017)7095 HAO] and Collaborative Innovation Center of Chinese Ministry of Education (grant no. 2020-39).

References