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Exploring m6A modifications in gastric cancer: from molecular mechanisms to clinical applications
European Journal of Medical Research volume 30, Article number: 98 (2025)
Abstract
The significance of m6A modifications in several biological processes has been increasingly recognized, particularly in the context of cancer. For instance, m6A modifications in gastric cancer (GC) have been significantly implicated in tumor progression, metastasis, and treatment resistance. GC is characterized by the differential expression of m6A regulators. High expression writers such as METTL3 and WTAP are associated with poor prognosis and aggressive clinical features. Conversely, low expression of METTL14 is linked to worse clinical outcomes, whereas elevated levels of demethylases, such as FTO and ALKBH5, correlate with better survival rates. These m6A regulators influence several cellular biological functions, including proliferation, invasion, migration, glycolysis, and chemotherapy resistance, thereby affecting tumor growth and therapeutic outcomes. The assessment of m6A modification patterns and the expression profiles of m6A-related genes hold substantial potential for improving the clinical diagnosis and treatment of GC. In this review, we provide an updated and comprehensive summary of the role of m6A modifications in GC, emphasizing their molecular mechanisms, clinical significance, and translational applications in developing novel diagnostic and therapeutic strategies.
Graphical Abstract
Introduction
Gastric cancer (GC), a malignant tumor, continues to be a significant global health concern [1, 2]. Although certain countries have witnessed a decline in incidence and mortality rates, it remains the third leading cause of cancer-related deaths worldwide [3, 4]. The outcome for GC is generally unfavorable, particularly when diagnosed at an advanced stage [5]. Traditional treatment methods, including surgery, chemotherapy, and radiotherapy, display limited effectiveness, especially in advanced cases. Recent progress has been witnessed in developing new therapies such as immune checkpoint inhibitors, cell-based immunotherapy, and cancer vaccines [6,7,8,9]. However, the majority of patients are diagnosed at later stages due to the lack of widespread early screening programs, which significantly affects treatment success and survival rates [10]. This emphasizes the critical need for identifying reliable biomarkers and developing novel, targeted therapeutic approaches to improve early diagnosis and treatment outcomes.
RNA modifications are essential post-transcriptional mechanisms that regulate gene expression and several cellular functions [11,12,13,14]. Among these modifications, N6-methyladenosine (m6A) is the most prevalent and extensively studied internal modification in eukaryotic messenger RNA (mRNA) [15, 16]. The m6A modification involves methylating the nitrogen-6 position of adenosine and is dynamically controlled by a set of enzymes, including methyltransferases ("writers"), demethylases ("erasers"), and RNA-binding proteins ("readers") [17,18,19,20,21]. The m6A modification has been implicated in multiple aspects of RNA metabolism, including splicing, export, stability, and translation, ultimately influencing the fate of RNA by determining whether it will be translated into proteins or degraded [17, 20, 22, 23]. The dynamic and reversible nature of m6A allows cells to finely tune gene expression in response to different signals and environmental changes [24]. In cancer, m6A modifications are frequently dysregulated, contributing to tumorigenesis and cancer progression [25,26,27,28,29]. For example, abnormal m6A methylation patterns can stabilize oncogenic RNAs or degrade tumor suppressor RNAs, thereby promoting cancer cell proliferation, migration, and invasion [30,31,32,33]. Research has indicated that m6A regulators are often dysregulated in GC tissues, with their expression correlating with several clinicopathological features [34].
In GC, m6A modifications has been implicated in tumorigenesis and cancer progression by affecting the stability and translation of oncogenic and tumor suppressor RNAs. This review summarizes the current understanding of m6A modifications in GC, focusing on their expression patterns, relationship with clinical characteristics, and biological functions. We hope to provide insights into potential therapeutic targets and prognostic biomarkers that could enhance the diagnosis and treatment of this malignancy by elucidating the role of m6A modifications in GC.
Molecular mechanism of m6A modification
The outline of m6A methylation
N6-methyladenosine (m6A) is the most prevalent internal modification found in eukaryotic messenger RNA (mRNA), impacting several aspects of RNA metabolism and function [15, 16]. This modification involves the methylation of the nitrogen atom at the sixth position of adenosine residues within RNA molecules. Notably, m6A is reversible and dynamically regulated, regulating gene expression and cellular processes [18, 35, 36]. The field of m6A research has significantly evolved since its discovery in the 1970s [37,38,39]. Initially, m6A was detected in different RNA species, including mRNA, transfer RNA (tRNA), ribosomal RNA (rRNA), and small nuclear RNA (snRNA) [15, 20, 22]. However, its biological significance has remained unclear for several decades, primarily due to the lack of sensitive detection methods, thus making comprehensive studies on m6A's distribution and functions challenging. The introduction of next-generation sequencing technologies in the early 2010s, particularly m6A-specific methylated RNA immunoprecipitation sequencing (MeRIP-seq or m6A-seq), revolutionized m6A research [40,41,42,43]. These advanced techniques have allowed researchers to accurately map m6A modification sites across the transcriptome, revealing the widespread presence and critical functional importance of m6A in eukaryotic cells. Although m6A is not randomly distributed, it frequently occurs in specific sequence contexts, such as the consensus motif DRACH [44,45,46]. Methylation is catalyzed by a complex of “writer” enzymes that transfer a methyl group from S-adenosylmethionine (SAM) to the N6 position of adenosine residues in RNAs [47,48,49]. These components work synergistically to deposit m6A marks in specific regions of mRNA transcripts, with implications for gene expression and cellular functions. The distribution and abundance of m6A are tightly controlled by these writers, as well as by “eraser” enzymes such as fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5), which remove the methyl group, thereby demethylating the RNA [50,51,52,53]. The biological functions of m6A modifications are mediated through several “reader” proteins that recognize and bind to m6A-modified RNAs. These reader proteins include the YTH-domain family proteins (such as YTHDF1, YTHDF2, and YTHDC1), which affect an RNA’s fate by regulating its stability, splicing, translation, and localization. These reader proteins act as key regulators, linking m6A modifications to diverse cellular processes, including differentiation, proliferation, and tumorigenesis.
m6A biogenesis and degradation
m6A methyltransferases (writers)
The m6A methylation occurs by a multicomponent methyltransferase complex, with METTL3 and METTL14 being the core components [54,55,56,57,58]. METTL3 acts as the catalytic subunit, transferring a methyl group from S-adenosylmethionine (SAM) to the N6 position of adenosine residues in RNAs, usually at specific consensus motifs (DRACH, where D = A/G/U, R = A/G, H = A/C/U) [47,48,49]. This enzymatic activity is essential for the recruitment of m6A across the transcriptome. METTL14, while lacking catalytic activity, serves as an RNA-binding platform that enhances METTL3’s methylation efficiency by properly positioning it for effective methylation [58,59,60]. WTAP (Wilms’ tumor 1-associating protein) is a key regulatory subunit that recruits the METTL3–METTL14 complex to specific RNA substrates [53, 61,62,63]. It stabilizes the interaction between METTL3 and METTL14 and facilitates the localization of the methyltransferase complex to nuclear speckles—the site of RNA processing. KIAA1429, also known as VIRMA, assists in substrate recognition and ensures methylation specificity, guiding the complex to particular regions of the transcriptome and influencing the spatial distribution of m6A modification [64,65,66]. RBM15 and RBM15B bind to the RNA-binding motif of the methyltransferase complex and enhance substrate specificity [67]. They interact with long non-coding RNAs (lncRNAs) and regulate X-chromosome inactivation and other RNA processing events.
m6A demethylases (erasers)
Demethylases can remove m6A modifications, indicating that these are reversible. FTO was the first identified m6A demethylase [68,69,70]. It oxidatively demethylates m6A residues, converting them back to adenosine through a stepwise oxidation process involving N6-hydroxymethyladenosine (hm6A) and N6-formyladenosine (f6A). The activity of FTO is crucial for regulating the dynamic nature of m6A modifications, influencing RNA stability and metabolism [71,72,73,74]. Another key m6A demethylase is ALKBH5 (AlkB Homolog 5), which directly removes m6A marks from RNAs [75,76,77]. ALKBH5 has been implicated in several biological processes, including spermatogenesis, by regulating mRNA export, stability, and translation efficiency [78]. The activities of these demethylases highlight the reversible nature of m6A modifications, allowing cells to rapidly adjust gene expression in response to physiological and environmental changes.
m6A reader proteins
Reader proteins recognize and bind to m6A-modified RNAs, mediating a wide range of downstream effects affecting RNA fate and function. YTHDF1 enhances the translation efficiency of m6A-modified mRNAs by interacting with translation initiation factors and promoting ribosome recruitment, thereby increasing protein synthesis from m6A-modified transcripts [79, 80]. YTHDF2 facilitates the decay of m6A-modified mRNAs by recruiting components of the mRNA degradation machinery, thereby selectively destabilizing and turning over target transcripts and regulating mRNA stability and gene expression [81, 82]. YTHDF3 coordinates the functions of YTHDF1 and YTHDF2, facilitating both the translation and degradation of m6A-modified mRNAs [83, 84]. It functions as an integrative factor, balancing mRNA stability and translation. YTHDC1 primarily functions in the nucleus, impacting mRNA splicing and export by recruiting splicing factors to m6A-modified pre-mRNAs and modulating exon inclusion or exclusion [85, 86]. In addition, YTHDC1 aids in exporting mature mRNAs to the cytoplasm. YTHDC2 has functions in both nuclear and cytoplasmic functions, regulating RNA stability and translation by interacting with components of the translation machinery and RNA decay pathways [87]. In addition, YTHDC2 is involved in germ cell development and meiosis by controlling the stability and translation of specific mRNAs. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP) are non-canonical m6A readers that recognize and bind to m6A-modified mRNAs, enhancing their stability and translation [88, 89]. IGF2BPs protect m6A-modified mRNAs from degradation by recruiting RNA-stabilizing complexes, thereby promoting sustained gene expression.
Role of m6A in post-transcriptional regulation
mRNA stability, translation, and splicing
The m6A modification is a major regulator of mRNA fate, impacting its stability, translation efficiency, and splicing (Fig. 1). YTHDF2, a well-characterized m6A reader, promotes mRNA decay by binding to m6A-modified mRNAs and recruiting the CCR4-NOT deadenylase complex [83, 84, 90]. This interaction removes the poly(A) tail and subsequent mRNA degradation, allowing cells to rapidly adjust mRNA levels in response to environmental and cellular signals, ensuring precise control over gene expression. Members of the insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family (IGF2BP1, IGF2BP2, IGF2BP3) recognize and bind to m6A-modified mRNAs, enhancing their stability by preventing degradation [88, 89]. This action extends the half-life of these mRNAs, allowing for their sustained translation and prolonged protein production, which is crucial for maintaining the expression of genes involved in cell growth, survival, and differentiation [89, 91]. YTHDF1 promotes the translation of m6A-modified mRNAs by interacting with translation initiation factors, such as eIF3, thereby facilitating ribosome recruitment to the mRNA [79]. This interaction increases the production of proteins from m6A-modified transcripts, which is essential during stress responses, cell growth, and differentiation [31]. YTHDC1, a nuclear m6A reader, is involved in alternative splicing by recruiting splicing factors to m6A-modified pre-mRNAs. It interacts with the splicing factor SRSF3 to promote exon inclusion and prevents the binding of SRSF10, which promotes exon skipping [85]. Thus, YTHDC1 modulates the splicing patterns of pre-mRNAs to produce different mRNA isoforms and contribute to transcriptome complexity. Furthermore [92, 93], m6A modifications can alter RNA secondary structures, generating or disrupting binding sites for splicing factors, thereby affecting the binding affinity of splicing regulators and modulating exon inclusion or exclusion.
Pivotal role of N6-methyladenosine (m6A) modification in post-transcriptional regulation. m6A modification is mediated by writers, erasers, and readers. These m6A regulators enhance the translation efficiency by facilitating ribosome recruitment. In addition, they affect alternative splicing by recruiting splicing factors. In non-coding RNAs, m6A stabilizes lncRNAs, modulating interactions with RNA-binding proteins and influencing gene expression. m6A increases circRNA stability, enables cap-independent translation, and functions as sponges for miRNAs or RNA-binding proteins. In addition, m6A facilitates the processing of pri-miRNAs into pre-miRNAs, ensuring proper miRNAs
Non-coding RNAs
Non-coding RNAs (ncRNAs), including lncRNAs, circRNAs, and miRNAs, do not encode proteins but are essential in regulating gene expression through processes like transcription, splicing, and translation. Recent studies show that m6A modifications impact the stability, function, and interactions of these ncRNAs, linking them to gene regulation and disease [94,95,96]. m6A modifications in long non-coding RNAs (lncRNAs) regulate gene expression by modulating their interactions with RNA-binding proteins and chromatin remodelers [97,98,99,100]. For instance, stabilization of lncRNA TP53TG1 by m6A modifications inhibits the oncogene Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), thereby suppressing the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway in GC [101]. This highlights the function of m6A-modified lncRNAs in tumor suppression and signaling regulation. m6A-modified lncRNAs can influence the chromatin state by recruiting chromatin-modifying enzymes to specific genomic regions, thereby altering histone modifications and chromatin accessibility, and regulating gene expression at the transcriptional level [102]. In addition, m6A modifications enhance the stability of circular RNAs (circRNAs) by protecting them from exonucleolytic degradation [23, 103, 104]. m6A-modified circRNAs can also be translated in a cap-independent manner, often through internal ribosome entry sites (IRES), contributing to protein diversity by producing functional proteins not encoded by linear mRNAs [105,106,107]. Beyond translation, m6A-modified circRNAs can function as sponges for microRNAs (miRNAs) or RNA-binding proteins, sequestering these molecules and regulating their activity [108]. This sequestration can impact gene expression networks and cellular signaling pathways. Furthermore, m6A modifications significantly contribute to miRNA biogenesis [109, 110]. The m6A modification facilitates the recognition and binding of the Microprocessor complex, which includes Drosha and DGCR8, to pri-miRNAs, promoting their cleavage into pre-miRNAs and ensuring proper miRNA maturation and function [111]. m6A modifications indirectly modulate miRNA-mediated gene silencing by influencing miRNA biogenesis [112,113,114]. Mature miRNAs target complementary mRNAs for degradation or translational repression, thereby fine-tuning gene expression. The regulation of miRNA biogenesis by m6A ensures that miRNAs are produced at appropriate levels and times, maintaining cellular homeostasis and response to environmental cues.
m6A modification regulators in gastric cancer
m6A methyltransferases (writers) in gastric cancer
The expression of METTL3 is markedly elevated in GC tissues in comparison to normal tissues [115,116,117,118]. The level of METTL3 expression is positively associated with clinicopathological characteristics, including lymph node metastasis, tumor size, TNM stage, and vessel invasion (Table 1) [115, 116]. Furthermore, Helicobacter pylori infection enhances its expression in a time-dependent manner [117]. Elevated METTL3 levels correlate with poorer overall survival (OS), disease-free survival (DFS), and post-progression survival (PPS) in patients with GC [115, 116, 118]. METTL3 expression is an effective predictor in GC, and a combination of TNM staging and METTL3 risk score significantly improves the AUC value to 0.796 [115]. Functionally, METTL3 facilitates GC proliferation, invasion, migration, and angiogenesis (Table 2) [115,116,117,118]. In addition, METTL3 upregulation significantly promotes tumor growth as well as lung and liver metastases in GC. Histone Acetyltransferase P300 (P300)-mediated Histone 3 Lysine 27 (H3K27) enhances METTL3 expression in GC [115]. METTL3-mediated m6A modification stabilizes HDGF mRNA via IGF2BP3, thereby sustaining HDGF expression (Fig. 2). Furthermore, METTL3 enhances glycolysis through the HDGF/GLUT4/ENO2 axis, promoting tumorigenesis and liver metastasis. METTL3 upregulates the expression of (Zinc Finger MYM-Type Containing 1) ZMYM1 in GC [116]. METTL3 boosts ZMYM1 mRNA expression through an m6A-HuR dependent pathway. The epithelial–mesenchymal transition (EMT), a critical process in cancer metastasis, is tightly regulated by m6A modifications. ZMYM1 interacts with the c-terminal binding protein/ lysine-specific demethylase 1/CoREST (CtBP/LSD1/CoREST) complex to repress epithelial cadherin (E-cadherin) transcription, triggering EMT and facilitating metastasis. The signal transducer and activator of transcription 5A (STAT5A) signaling pathway, frequently activated in GC, is another target of m6A modifications Knocking down STAT5A significantly inhibits GC growth and metastasis. METTL3 introduces m6A modifications within the CDS region of STAT5A, whereas IGF2BP2 stabilizes the STAT5A mRNA in an m6A-dependent manner. METTL3 promotes GC progression by regulating STAT5A and Kruppel-like factor 4 (KLF4). Moreover, suppressing A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) reverses the inhibition of HUVEC tube formation and proliferative ability caused by METTL3 deficiency [118]. METTL3 reduces ADAMTS9 expression in an m6A- YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-dependent pathway. Altogether, METTL3 facilitates GC progression through the ADAMTS9/PI3K/AKT axis. These findings highlight METTL3 as a central regulator of multiple oncogenic pathways in GC.
Mechanism of METTL3-mediated m6A modifications in gastric cancer (GC) progression. METTL3 sustains HDGF levels by stabilizing HDGF mRNA through IGF2BP3, enhancing glycolysis via (glucose transporter type 4) GLUT4 and (enolase 2) ENO2, thereby driving tumorigenesis and liver metastasis. Moreover, METTL3 increases ZMYM1 expression through an m6A-HuR-dependent mechanism. ZMYM1 subsequently recruits the CtBP/LSD1/CoREST complex to repress the E-cadherin promoter, promoting GC progression. In addition, METTL3 adds m6A marks to the CDS region of STAT5A, and IGF2BP2 stabilizes STAT5A mRNA in an m6A-dependent fashion, facilitating GC progression by regulating KLF4. Furthermore, METTL3 decreases ADAMTS9 expression through an m6A-YTHDF2-dependent pathway, advancing GC progression via ADAMTS9-mediated PI3K/AKT signaling
METTL14 is expressed at low levels in GC tissues and cells, and its expression is inversely correlated with tumor size, histological grade, and TNM stage [108, 119, 120]. Consequently, patients with low METTL14 expression in GC exhibit shorter OS. The overexpression of METTL14 suppresses cell proliferation, viability, colony formation, migration, and invasion. In vivo, METTL14 inhibits tumor growth and lung metastasis [108, 119]. METTL14 exerts its effects through m6A-dependent modification of circORC5 [108]. Specifically, the depletion of circORC5 reduces colony formation and invasion capabilities. The expression of circORC5 is elevated in GC tissues and is negatively associated with patient prognosis. Furthermore, METTL14 mediates circORC5 to regulate the miR-30c-2-3p/ AKT serine/threonine kinase 1 substrate 1 (AKT1S1) axis. METTL14 can bind to the methylation sites of TATA-box binding protein (TBP)-associated factor 10, promoting m6A methylation and subsequent degradation of TAF10 and consequently inhibiting the malignant progression of GC [119]. Moreover, the overexpression of METTL14 can suppress GC cell biological functions by deactivating the PI3K/AKT/mTOR and EMT pathways [120].
WTAP is upregulated in GC tissues and cells [121,122,123]. It possesses a high diagnostic accuracy for GC (AUC = 0.779) [121]. Elevated WTAP expression is significantly associated with reduced overall survival (OS) in patients with GC [121, 122]. Functionally, WTAP promotes the proliferation and glycolytic capacity of GC cells [121]. In addition, WTAP enhances chemotherapy resistance to DDP and CTX as well as radiotherapy resistance in GC cells [122]. The knockdown of WTAP reverses the resistance of GC cells to DDP and CTX. FAM83H Antisense RNA 1 (FAM83H-AS1) facilitates cell proliferation, migration, and invasion, and WTAP silencing reverses the oncogenic effects of FAM83H-AS1 overexpression in GC cell migration, proliferation, and invasion [123]. In addition, silenced WTAP inhibited tumor growth in vivo [121]. Hexokinase 2 (HK2) is identified as a target of WTAP, with WTAP promoting its expression by increasing HK2 m6A methylation [121]. In addition, WTAP promotes EMT by upregulating the expression of transforming growth factor-β (TGF-β) in GC [122]. Furthermore, WTAP triggers the upregulation of FAM83H-AS1 via m6A modification [123]. WTAP-mediated FAM83H-AS1 promotes GC progression through m6A modification, highlighting the complex function of WTAP in GC malignancy.
METTL16 is highly expressed in GC cells and tissues [124, 125]. Specifically, the expression of METTL16 is positively associated with larger tumors and regional lymph node metastasis in patients with GC [125]. Moreover, patients with GC and elevated METTL16 protein levels report significantly improved OS and DFS [124, 125]. Functionally, silenced METTL16 inhibits GC cell proliferation by restraining the G1/S phase [125]. METTL16 could promote tumor growth in vivo. In addition, higher copper levels in patients with GC are linked to shorter OS and DFS [124]. Copper is also associated with increased cell proliferation and higher inflammation-related biomarkers, indicating its function in GC progression. Cuproptosis, a recently identified form of regulated cell death driven by copper-dependent mitochondrial protein aggregation and lipoylation [126]. Furthermore, METTL16 could promote GC progression by enhancing cuproptosis [124].
Specifically, METTL16 promotes cuproptosis by upregulating the expression of Ferredoxin 1 (FDX1) [124]. Copper stress induces METTL16-K229 lactylation, enhancing its activity. Sirtuin 2 (SIRT2) delactylates and inhibits METTL16. A combination of elesclomol and AGK2, an SIRT2 inhibitor, induces cuproptosis in gastric tumors. This suggests a potential GC therapy using copper ionophores and a SIRT2-specific inhibitor [124]. Furthermore, Cyclin D1 is a downstream target of METTL16 that regulates the GC cell cycle by reducing Cyclin D1 levels, thereby affecting cell proliferation [125].
m6A demethylases (erasers) in gastric cancer
The expression of FTO, which is upregulated in GC tissues, is significantly associated with pathological node stage (pN stage), pathological tumor stage (pT stage), (tumor, node, metastasis stage) TNM stage, liver invasion, nerve invasion, tumor size, and lymph node metastasis (LNM) in patients with GC [127,128,129,130]. Higher FTO expression correlates with poorer prognosis in these patients [127,128,129,130]. FTO promotes cell proliferation and motility in vitro. In addition, the knockdown of FTO suppresses mitochondrial fission/fusion and metabolism, possibly leading to reduced ATP replenishment and consequently limiting cancer cell growth [127]. In vivo, FTO knockdown significantly inhibits tumor growth, lymph node metastasis, and lung metastasis [127, 130]. FTO directly targets and inhibits the expression of caveolin-1 mRNA [127]. FTO promotes GC metastasis by stabilizing integrin-β 1(ITGB1) mRNA in an m6A-dependent manner, activating the ITGB1–focal adhesion kinase (FAK) signaling pathway [128]. Moreover, FTO regulates Specificity Protein 1 (SP1) expression by demethylating its RNA [129]. SP1 is upregulated in patients with GC and predicts poor prognosis. Silencing SP1 inhibits cell migration, invasion, and tumor growth in vivo and significantly downregulates aurora kinase B (AURKB) expression in GC cells. Ataxia-telangiectasia mutated (ATM) is a downstream target of both SP1 and AURKB. The FTO–SP1–AURKB–ATM axis regulates GC progression by targeting the P38/P53 pathway [129]. Furthermore, FTO enhances PI3K/Akt signaling to promote GC progression [130].
ALKBH5 is significantly upregulated in GC tissues [131,132,133]. The expression of ALKBH5 is positively correlated with multiple clinical features, such as invasion depth, TNM stage, and lymphatic metastasis [133]. Patients in the high ALKBH5 expression group have shorter survival times [132, 133]. Reduced ALKBH5 expression significantly inhibits GC cell proliferation, invasion, metastasis, vasculogenic mimicry (VM) formation, and cell spheroid formation [131,132,133]. The overexpression of ALKBH5 increases tumor growth and enhances lung and liver metastases [133]. Nuclear enriched abundant transcript 1 (NEAT1), which is rich in m6A modifications, is a target biomarker of ALKBH5 (Fig. 3) [131]. The levels of NEAT1 reduce with the knockdown of ALKBH5. ALKBH5 regulates NEAT1 levels through demethylation, and upregulated expression of NEAT1 subsequently elevates enhancer of zeste 2 (EZH2) expression, causing a malignant phenotype [131]. Moreover, ALKBH5-induced zinc finger with KRAB and SCAN domains 3 (ZKSCAN3) expression could promote vascular endothelial growth factor A (VEGFA) expression, contributing to MNNG-induced GC progression [132]. Furthermore, ALKBH5 promotes GC progression by upregulating janus kinase 1 (JAK1) expression in an m6A-YTHDF2-dependent manner, thereby activating the JAK/STAT signaling pathway [133].
Mechanism of ALKBH5-mediated m6A demethylation in regulating gastric cancer (GC) progression. ALKBH5 removes m6A modifications from NEAT1, causing its overexpression and subsequently elevating EZH2 levels, which promote a malignant phenotype. In addition, ALKBH5 influences ZKSCAN3 expression through m6A demethylation, activating VEGFA transcription and promoting MNNG-induced GC progression. Moreover, ALKBH5 facilitates GC development by enhancing JAK1 mRNA levels in an m6A-YTHDF2-dependent manner, with regulation mediated by LINC00659. Furthermore, ALKBH5 reduces protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) expression through m6A demethylation, whereas IGF2BP3 stabilizes PKMYT1 mRNA by interacting with its m6A modification sites
Another study reported that ALKBH5 expression is decreased in GC tissues and is intricately related to tumor stage, lymph node metastasis, and distant metastasis [134]. ALKBH5 expression is negatively correlated with prognoses in GC. Receiver operating characteristic (ROC) curves indicate that ALKBH5 is highly sensitive and specific for the clinical diagnosis of GC. Functionally, ALKBH5 inhibits GC invasion and migration [134]. RIP and RNA pulldown assays have demonstrated the binding between ALKBH5 and PKMYT1 transcript, indicating that PKMYT1 functions downstream of ALKBH5. PKMYT1 promotes GC invasion and migration in an m6A-dependent manner, whereas ALKBH5 downregulates PKMYT1 expression through m6A demethylation. IGF2BP3 stabilizes PKMYT1 mRNA by binding to its m6A modification sites [134]. These contrasting findings suggest a complex and context-dependent function for ALKBH5 in GC progression, necessitating further investigation to clarify its precise functions and implications in GC.
m6A reader proteins in gastric cancer
N-Methyl-N-nitrosourea (MNU) is a carcinogenic alkylating agent with no requirement for metabolic bioactivation [135]. Tang et al. established an in vitro model of MNU-induced malignant gastric epithelial cells [136]. (N-Nitroso-n-methylurea stimulation) MNU stimulation could enhance the expression of YTHDF1 in a dose-dependent manner. In addition, in vivo exposure to MNU caused elevated YTHDF1 expression in GC. Silencing YTHDF1 inhibited cell proliferation and colony formation in MNU-induced malignant gastric epithelial cells [136].
Heat shock 70 kDa protein family member 1 (HSPH1) has been identified as a target of m6A modification by YTHDF1 in MNU-induced malignant transformed cells. The knockdown of HSPH1 inhibited cell proliferation, migration, and colony formation in GC cells. YTHDF1 promotes GC progression by regulating the expression of HSPH1 protein [136].
IGF2BP1 is upregulated in GC tissues and cells [137, 138]. Patients with higher levels of IGF2BP1 exhibit poorer disease-free survival (DFS) and overall survival (OS). The upregulation of IGF2BP1 promotes the proliferation and aerobic glycolysis in GC cells [137, 138]. IGF2BP1 weakens the function of CD8+ T cells and promotes immune escape in GC cells [138]. The knockdown of IGF2BP1 represses tumor growth in vivo. c-Myc is a target of IGF2BP1, with IGF2BP1 enhancing the stability of c-Myc mRNA, thereby accelerating the aerobic glycolysis in GC cells [137]. In addition, IGF2BP1 interacts significantly with programmed cell death ligand 1 (PD-L1) in GC cells [138]. The overexpression of IGF2BP1 promotes PD-L1 expression and tumor immune escape by facilitating the m6A modification of PD-L1.
However, Chen et al. reported that IGF2BP1 is markedly downregulated in GC tissues [139]. Furthermore, lower levels of IGF2BP1 are significantly linked to histological differentiation, lymph node metastasis, and TNM stages in patients with GC. This reduced expression of IGF2BP1 is associated with significantly shorter overall survival in patients with GC [139]. Moreover, IGF2BP1 suppresses GC cell proliferation and colony formation. Contrarily, silenced IGF2BP1 significantly promotes tumor growth in vivo. Furthermore, MYC (c-myc proto-oncogene) mRNA is identified as a target transcript of IGF2BP1 in GC cells. IGF2BP1 inhibits the expression of MYC in an m6A-dependent manner [139]. These studies present conflicting findings regarding the function of IGF2BP1 in GC. Further research is warranted to reconcile these differences and elucidate the precise function of IGF2BP1 in GC.
HnRNPA2B1 is highly expressed in GC cells and tissues [140,141,142]. The expression of hnRNPA2B1 is markedly associated with differentiation grades, TNM stages, nerve invasion, microvascular invasion, and metastasis [140, 142]. In addition, patients with elevated hnRNPA2B1 levels display a significantly worse response to chemotherapy compared to those with lower levels of hnRNPA2B1 [140, 141]. Elevated hnRNPA2B1 expression is linked to poorer overall survival (OS), first progression survival (FPS), and post-progression survival (PPS) in patients with GC [140,141,142]. The downregulation of hnRNPA2B1 sensitizes GC cells to vincristine (VCR) and 5-fluorouracil (5-Fu), inhibiting cell proliferation in chemo-resistant settings [140]. hnRNPA2B1 enhances the stemness properties of GC cells and promotes chemoresistance in vivo. Furthermore, it modulates metabolic reprogramming, including glucose uptake, pyruvate and lactate production, and NADP + /NADPH ratios, in response to Helicobacter pylori infection in GC [141]. Knockdown of hnRNPA2B1 significantly reduces H. pylori-induced migration and invasion of GC cells and markedly promotes liver metastasis in vivo. In addition, silencing hnRNPA2B1 increases CDDP chemosensitivity both in vitro and in vivo, reduces cancer stem cell characteristics, and causes cisplatin resistance in GC cells [142].
Altogether, hnRNPA2B1 upregulates NEAT1 in an m6A modification-dependent manner, promoting GC drug resistance via NEAT1 [140]. hnRNPA2B1 enhances stemness properties and exacerbates chemoresistance through the Wnt/β-catenin pathway in GC. Additionally, it promotes metabolic reprogramming and invasion in Helicobacter pylori-infected GC cells by regulating NF-κB signaling [141]. In addition, cytoplasm-anchored hnRNPA2B1 coordinates with PABPC1 to facilitate the translation of CIP2A, dihydrolipoamide S-acetyltransferase (DLAT), and glutathione peroxidase 1 (GPX1). Furthermore, hnRNPA2B1 co-expresses with several core spliceosome components to regulate the alternative splicing of baculoviral IAP repeat-containing 5 (BIRC5), an anti-apoptotic factor [142].
Clinical applications of m6A modification in gastric cancer
Diagnostic and prognostic roles of m6A modification in gastric cancer
The expression and activity of m6A-related enzymes and proteins, including writers, erasers, and readers, are involved in the diagnosis and prognosis of GC [143,144,145]. Dysregulation of m6A-related genes, such as METTL3, METTL14, FTO, and ALKBH5, is commonly observed in GC tissues [115, 116, 120, 127, 133]. High expression of METTL3 and WTAP is linked to poor prognosis, advanced tumor stages, and metastasis, whereas low levels of METTL14 correlate with adverse clinical outcomes [116, 120, 121]. These m6A modifications affect key cellular processes such as proliferation, invasion, migration, glycolysis, and chemotherapy resistance, providing valuable insights for diagnostic and prognostic purposes in GC [121, 136, 141]. Integrating m6A modification assessments with conventional biomarkers can improve the accuracy of GC diagnostics. A combination of m6A-related gene expression profiles with traditional biomarkers can enhance the sensitivity and specificity of GC detection [146]. In addition, m6A modification patterns can stratify patients into different risk groups, facilitating the development of personalized treatment plans. Studies have demonstrated that the m6A methylation status of specific mRNAs is correlated with patient outcomes [124, 134]. For example, m6A modifications on key oncogenes or tumor suppressors can impact their expression and functional activities, affecting tumor growth and metastasis [30, 115]. Thus, evaluating the m6A landscape in patients with GC provides valuable prognostic information and guides clinical decision-making.
Therapeutic strategies targeting m6A modification
Targeting the m6A methyltransferase complex (METTL3/METTL14) is a potential therapeutic strategy in GC [27, 147, 148]. Inhibitors blocking the catalytic activity of METTL3 can reduce m6A modifications on oncogenic mRNAs, destabilizing and decreasing translation [115,116,117,118]. This approach can effectively inhibit tumor growth and progression. Small molecule inhibitors of METTL3, such as STM2457, have demonstrated antitumor activity in preclinical models and are currently being evaluated in clinical trials [55, 149]. However, the long-term effects and potential toxicity of METTL3 inhibitors need further evaluation. In addition, inhibiting the m6A demethylase FTO can increase m6A levels on target mRNAs, thereby stabilizing and enhancing translation [127,128,129]. For instance, meclofenamic acid (MA), an FTO inhibitor, has been demonstrated to suppress tumorigenesis by modulating the expression of critical genes involved in cell proliferation and survival [150,151,152]. Nevertheless, the application of FTO inhibitors may elicit off-target effects, as FTO also modulates non-coding RNAs and participates in various cellular processes beyond mRNA stability. These activities could potentially disrupt cellular homeostasis, leading to unintended side effects. While these inhibitors are being actively investigated for their ability to enhance the efficacy of current cancer therapies, further studies are necessary to fully assess their specificity and long-term safety profiles. These inhibitors are being explored for their potential to enhance the efficacy of existing cancer therapies. Similarly, targeting ALKBH5 can increase m6A modifications on mRNAs, promoting their stability and translation [131,132,133,134]. In addition, ALKBH5 inhibitors are being investigated for their ability to sensitize cancer cells to chemotherapeutic agents and improve treatment outcomes. m6A modifications significantly contribute to the development of chemotherapy resistance in GC. Altered m6A methylation patterns can affect the expression of genes involved in drug metabolism, DNA repair, and apoptotic pathways, reducing sensitivity to chemotherapeutic agents [153, 154]. A combination of m6A modulators with conventional chemotherapeutic agents can overcome resistance and enhance treatment efficacy. For example, co-administering FTO inhibitors with DNA-damaging agents can hinder the repair of chemotherapeutic-induced DNA lesions, causing increased cancer cell death [155]. Developing targeted delivery systems, such as nanoparticles or liposomes, to deliver m6A modulators specifically to tumor cells can maximize their therapeutic effects while minimizing off-target toxicity [156, 157]. The m6A modification profiles can be used as potential biomarkers to predict patient response to chemotherapy and tailor treatment regimens and improve clinical outcomes [122, 140]. Patients with high levels of m6A-related resistance genes could benefit from combination therapies including m6A inhibitors.
With the advancement of CRISPR/dCas technologies, their potential in regulating m6A modifications has garnered increasing attention. Among these, the CRISPR/dCas13 system, as a precise RNA-targeting tool, has been applied to modulate RNA fate and m6A modifications [158]. Preliminary studies have explored the feasibility of leveraging this technology for site-specific regulation of m6A modifications [159, 160]. By fusing dCas13 with specific effectors, precise control of m6A modifications at specific sites can be achieved, thereby modulating the expression of cancer-related genes. These technologies hold great promise, particularly in enabling precise control over RNA transcription and translation, offering novel opportunities for targeted therapies in gastric cancer. Emerging research has begun to demonstrate the potential applications of CRISPR/dCas13 in gastric cancer. By coupling dCas13 proteins with m6A methyltransferases (such as METTL3), the system enables site-specific methylation of lncRNAs associated with gastric cancer, providing crucial insights into the functional roles of RNA modifications in tumorigenesis [161]. Furthermore, CRISPR/dCas13 technology shows significant potential in regulating gastric cancer stem cell maintenance, RNA–protein interactions, and dynamic signaling pathways. However, challenges such as ensuring target specificity, improving delivery efficiency, and addressing long-term safety remain significant hurdles. With further optimization of delivery vectors and guide RNA design, CRISPR/dCas13 is poised to become a powerful tool for investigating RNA modifications and developing targeted therapeutic strategies for gastric cancer, paving the way for advances in precision medicine.
Conclusions and perspectives
Research on N6-methyladenosine (m6A) modifications has opened new avenues in understanding the molecular mechanisms underlying gastric cancer (GC) progression and its resistance to therapy. Dysregulation of m6A-related enzymes and proteins, including methyltransferases (writers), demethylases (erasers), and readers, has been implicated in the development and metastasis of GC. High expression of METTL3 and WTAP is associated with poor prognosis and aggressive tumor characteristics, whereas low levels of METTL14 correlate with worse clinical outcomes. Conversely, elevated levels of FTO and ALKBH5 are linked to better survival rates, highlighting the complex and context-dependent roles of these enzymes in GC. m6A modifications serve as critical diagnostic and prognostic biomarkers for GC. Integrating m6A-related gene expression profiles with conventional biomarkers not only enhances the sensitivity and specificity of diagnostic tools but also enables more precise patient stratification. This stratification allows for personalized treatment plans, improving diagnostic accuracy and therapeutic outcomes. Furthermore, profiling the m6A landscape in GC patients can offer deeper insights into disease progression, providing valuable prognostic information and guiding clinical decision-making.
Therapeutic strategies targeting m6A modifications represent promising avenues for advancing GC treatment. Inhibitors of m6A methyltransferases, such as METTL3/14, and demethylases, such as FTO and ALKBH5, are being developed to modulate m6A levels on oncogenic mRNAs, thereby inhibiting tumor growth and enhancing the efficacy of current therapies. These strategies can overcome chemotherapy resistance, a major challenge in GC treatment, by targeting the molecular pathways involved in drug metabolism, DNA repair, and apoptosis. Despite the significant progress made in understanding the function of m6A modifications in GC, several challenges and opportunities remain. Future research should focus on elucidating the precise molecular mechanisms of m6A modifications in GC, particularly the interplay between m6A-related proteins and their RNA targets. Mechanistic studies will not only enhance our understanding of m6A biology, but also uncover novel therapeutic targets. Similarly, it is crucial to identify and validate m6A modification profiles as reliable biomarkers for early detection, prognosis, and therapeutic response in GC. The development of these biomarkers can significantly improve disease management and patient outcomes. From a therapeutic perspective, developing specific and potent inhibitors or activators of m6A-related enzymes is essential. Exploring combination therapies involving m6A modulators and conventional chemotherapeutic agents may further enhance treatment efficacy. To translate these findings into clinical practice, rigorous clinical trials are needed to assess the safety, efficacy, and long-term outcomes of m6A-targeted therapies in GC patients. Such efforts are vital for bridging the gap between preclinical research and clinical applications, ultimately enabling precision medicine in gastric cancer treatment.
The study of m6A modifications has revolutionized our understanding of gastric cancer by uncovering their critical roles in gene expression regulation, tumor progression, and therapy resistance. These findings not only establish m6A-related enzymes and modification profiles as promising biomarkers, but also pave the way for novel therapeutic strategies targeting m6A pathways. Despite current challenges, advancements in mechanistic insights, biomarker validation, and therapeutic development will undoubtedly transform the management of gastric cancer, bringing us closer to the realization of precision medicine. Future research must continue to integrate molecular biology, translational medicine, and clinical trials to fully harness the potential of m6A modifications in combating this complex disease.
Data availability
No datasets were generated or analysed during the current study.
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Li, P., Fang, X. & Huang, D. Exploring m6A modifications in gastric cancer: from molecular mechanisms to clinical applications. Eur J Med Res 30, 98 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40001-025-02353-5
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40001-025-02353-5