Gastric cancer (GC) persists as a leading cause of global cancer morbidity and mortality, with its pathogenesis intricately linked to epigenetic dysregulation. Emerging research specifies the novelty of these mechanisms—including DNA methylation, histone modifications, non-coding RNAs (ncRNAs), and RNA modifications—in GC initiation, progression, and therapeutic resistance. This review systematically examines key epigenetic mechanisms in GC, dissect the therapeutic implications as diagnostic biomarkers and therapeutic targets. Key insights include (1) aberrant methylation of tumor suppressor genes (e.g., CDH1, RUNX3): in early carcinogenesis; (2) histone lactylation and acetylation modulating immune evasion (3) ncRNAs (e.g., miR-21, HOTAIR); as promising biomarkers; and (4) m6A RNA modification in chemotherapy resistance. We further discuss translational applications of epigenetic biomarkers in liquid biopsies and targeted therapies (e.g., DNMT/HDAC inhibitors). Integrating multi-omics and epigenetic editing technologies may advance precision medicine in GC.
biomarkerDNA methylationepigeneticsgastric cancerhistone modificationnon-codingRNAThe author(s) declared that financial support was not received for this work and/or its publication.section-at-acceptanceOncology Reviews: ReviewsIntroduction
Epigenetic modifications encompass heritable changes in gene activity without altering the DNA sequence, regulating gene expression through mechanisms such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) interactions (1–4). These reversible modifications serve as molecular switches, enabling spatiotemporal control of gene expression and cellular phenotypes. In gastric cancer (GC), epigenetic dysregulation contributes to precancerous lesions, tumor progression, and therapeutic resistance, offering novel avenues for early intervention and personalized therapy.
GC ranks as the fifth most common malignancy globally, with nearly one million new cases annually and a mortality rate ranking fifth among all cancers (5–7). Due to its insidious early symptoms and lack of specific reliable biomarkers, approximately 60% of patients are diagnosed at advanced stages, resulting in a 5-year survival rate below 30%. The role of biomarkers in GC classification has evolved fundamentally, transitioning from irrelevance to central importance. Initially, classification was solely based on morphology (e.g., Lauren classification), with no role for biomarkers. The paradigm shifted with the validation of HER2 as the first actionable predictive biomarker for targeted therapy. The landmark TCGA project in 2014 subsequently established a molecular taxonomy, elevating biomarkers like EBV and MSI to a diagnostic role for defining distinct disease subtypes. In current practice, the role of biomarkers is decisively actionable. The simultaneous testing for a panel of biomarkers (e.g., HER2, PD-L1, MSI) enables clinicians to directly select the most effective targeted or immunotherapy regimens for individual patients. This progression signifies a shift in classification from purely descriptive morphology to a system that directly informs personalized treatment strategies.
Emerging evidence highlights the critical role of epigenetic regulation—including DNA methylation, histone modifications, ncRNAs, and RNA modifications—in GC initiation, progression, and microenvironment remodeling through reversible mechanisms. This review is structured as follows: First, we examine aberrant DNA methylation in early carcinogenesis and progression. Next, we discuss histone modifications, chromatin remodeling, and the roles of non-coding RNAs. We then explore RNA modifications, particularly m6A, in GC pathogenesis. Finally, we evaluate the clinical translation of epigenetic biomarkers and outline future research directions.
DNA methylation
DNA methylation, catalyzed by DNA methyltransferases (DNMTs), involves the addition of a methyl group to cytosine at CpG sites, forming 5-methylcytosine (5-mC), which typically inhibits gene expression in cancer (Figure 1); (8). Aberrant DNA methylation is not only a characteristic of end-stage GC, but also an early and driving event in the pathogenesis of GC.
Promoter DNA methylation leads to gene suppression, contributing to the pathogenesis of gastric cancer.
Illustration of DNA methylation causing gene silencing, leading to stomach cancer. It shows DNA undergoing methylation at the promoter region, preventing target gene expression (e.g., APC, CHD1, p16), resulting in cancerous cell growth in the stomach.DNA methylation in early gastric carcinogenesis
In precancerous lesions (such as chronic atrophic gastritis, intestinal metaplasia), promoter hypermethylation of tumor suppressor genes (e.g., p16, MLH1, APC) is observed (9–11). For instance, CDH1 (E-cadherin) methylation occurs in 30%–50% of premalignant lesions, impairing cell adhesion (12). The mechanisms by Helicobacter pylori (H. pylori) infection activates DNMT1 and inflammatory pathways (e.g., NF-κB), inducing genome-wide methylation aberrations that persist as “epigenetic memory” even after eradication contributes to gastric carcinogenesis are associated with activating DNMT1 and inflammatory signaling pathways (e.g., NF-κB), inducing genome-wide methylation aberrations that persist as “epigenetic memory” even after eradication (13–15). Similarly, EBV infection also shapes the gastric methylome distinctly (16–18). Both pathogens can activate the PI3K/AKT signaling pathway to promote gastric epithelial proliferation (19). Environmental factors (e.g., smoking, diet)can also promote hypermethylation of hub genes including MAPK1 and CDK1 contributing to gastric carcinogenesis (20, 21).
Dynamic DNA methylation changes in tumor progression
Aberrant methylation affects diverse functional gene groups, including tumor suppressors, DNA repair genes, hox genes, and cell cycle regulators collectively driving GC progression (22). Early-stage localized hypermethylation of tumor suppressors like RUNX3 presents opportunities for demethylating agents. In advanced GC, hypomethylation coexists with hypermethylation. For instance, TIMP3 demethylation promotes tumor invasion, whereas PTEN hypermethylation accelerates metastatic progression (23–25). Notably, circulating tumor DNA (ctDNA) methylation in metastatic GC carries metastasis-associated methylation signatures (26).
Summary and future perspectives
Research on DNA methylation in GC has decisively shifted from foundational discovery to clinical translation. Among the plethora of methylated genes reported, a few have emerged with superior merit for specific clinical applications, largely driven by advancements in the last 6 years. For early detection, the most promising and clinically adopted biomarkers are RNF180 and Septin9. Their methylation assays have been endorsed by China’s Expert Consensus and are available as NMPA-approved commercial kits for high-risk population screening (27). For prognostic stratification and monitoring, methylation of SPG20 and FBN1 robustly correlates with poor outcomes, while CPNE1 methylation status shows predictive value for chemotherapy response (28). Technologically, the analysis of EV-derived DNA methylation represents a major innovation for non-invasive detection, while single-cell methylome sequencing is set to resolve tumor heterogeneity (29). In our view, the future lies not in discovering more methylated genes, but in validating and integrating these top-tier candidates (e.g., RNF180/Septin9 for screening, SPG20/FBN1 for prognosis) into multi-analyte liquid biopsy panels to achieve the required sensitivity and specificity for early-stage GC detection (30).
Histone modifications
Chromatin, composed of DNA, histones, and non-histone proteins, is dynamically regulated by post-translational modifications (e.g., acetylation, methylation, lactylation, phosphorylation, ubiquitination). Histone modifications form a sophisticated regulatory network by exerting crucial effects through coordinated gene expression in GC (Figure 2).
Epigenetic mechanisms of histone modification: acetylation, methylation, lactylation, phosphorylation, and ubiquitination.
Illustration depicting histone modification. A chromosome connects to chromatin fibers consisting of DNA wrapped around histone proteins. The histone tail displays action by writer, reader, and eraser proteins, indicating modification processes.Functional integration of histone modifications
In the GC microenvironment, lactate accumulation (Warburg effect) drives histone H3K18 lactylation (H3K18la), a recently discovered modification that links cellular metabolism directly to epigenetic regulation. The merit of H3K18la as a biomarker stems from its strong correlation with aggressive disease features, including poor prognosis, immune evasion, and metastasis (31–34). Mechanistically, H3K18la facilitates tumor proliferation and metastasis by recruiting M2 macrophages and activating the VCAM1-AKT pathway (35). While the direct detection of histone lactylation in patient blood remains challenging, its upstream driver (lactate) is readily measurable, and the downstream transcriptional signatures it induces (e.g., VCAM1) hold immediate promise as surrogate liquid biopsy biomarkers. This positions lactylation not only as a compelling therapeutic target but also as the conceptual foundation for a new class of metabolic-epigenetic biomarkers.
Acetylation: H. pylori carcinogenesis is linked to H4 acetylation in the p21 promoter region (36, 37). H3K9 and H4K16 hypoacetylation strongly associated with poorly differentiated GC (37, 38). Overexpression of histone deacetylases (HDACs) correlates with advanced GC stages may predict immunotherapy response (39, 40).
Methylation: Elevated levels of H3K27, H3K4, and H3K9 methylation collectively promote tumor initiation and progression. The histone methylation regulators EZH2, KDM6A, and KDM6B drive GC susceptibility through synergistic control of H3K27me (41). Lysine-specific demethylase 1 (LSD1) mediated demethylation suppresses antitumor immunity in GC by upregulating exosomal PD-L1 to suppress T-cell responses (42). Histone methyltransferase SETD1A interacts with HIF1α to enhance glycolysis and promote GC progression (43).
Phosphorylation: Histone phosphorylation regulates key processes including DNA repair and apoptosis (44): H. pylori infection induces oncogenic H3S10 phosphorylation (45), while overexpression of phosphorylated H3 predicts inferior survival (46).
Ubiquitination: Histone ubiquitination modulates chromatin structure and degradation, with H2B ubiquitination levels correlating with disease progression (47, 48).
Other histone modifications, such as SUMOylation and ADP-ribosylation, also contribute to GC epigenetics, though their roles are less characterized and warrant further investigation.
Summary and future perspectives
Although numerous investigations underscore the significance and therapeutic potential of post-translational histone modifications, their downstream targets remain largely elusive. Consequently, research continues to prioritize the exploration of modification targets and pathways, while clinical translation remains limited.
Technologically, Chromatin Immunoprecipitation with highthroughput sequencing (ChIP-seq) enables genome-wide mapping of epigenetic marks; Cleavage Under Targets and Tagmentation (CUT&Tag) offers a high-resolution technique for profiling histone-DNA interactions; and CUT&Tag with tagmentation-based bisulfite sequencing (CUT&Tag-BS) permits simultaneous detection of histone modifications and DNA methylation, particularly valuable for limited samples. Looking forward, integrating these advanced in situ protein-DNA interaction profiling technologies will facilitate systematic elucidation of genome-wide histone modification landscapes and 3D chromatin dynamics in GC.
Chromatin remodeling
Chromatin remodeling complexes, including SWI/SNF and CHD family members, dynamically regulate nucleosome positioning and chromatin accessibility to drive GC progression. These ATP-dependent complexes function as structural effectors of epigenetic regulation and engage in reciprocal crosstalk with DNA methylation, mutually shaping their genomic localization and activity (49). These structural alterations represent fundamental mechanisms underlying gastric tumorigenesis and present promising targets for epigenetic-based therapeutic interventions.
Key remodeling components demonstrate distinct pathological roles: ARID1A (a SWI/SNF subunit) is frequently mutated in GC, with its loss driving malignant progression, immune microenvironment remodeling, and therapy resistance (50–52). CHD4 enhances chemoresistance by stimulating drug efflux and reducing intracellular cisplatin accumulation, while CHD5 acts as a pan-cancer tumor suppressor (53, 54).
Although SWI/SNF complex mutations have been elucidated more recently than those of classic oncogenes, the remarkable heterogeneity in how SWI/SNF dysfunction drives tumorigenesis presents both a challenge and a unique opportunity for developing precision epigenetic therapies in GC.
Non-Coding RNAs
Although less than 2% of the human genome encodes proteins, the vast majority of transcripts consist of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These ncRNAs play crucial roles in GC development by modulating chromatin architecture and gene expression (55, 56); (Figure 3).
Regulatory functions of non-coding RNAs in GC by modulating gene expression.
Illustration depicting RNA processes in a cell. On the left, a sequence shows DNA transcription into RNA and protein synthesis. On the right, different RNA types are labeled: miRNA, circRNA, and lncRNA, each with examples like miR-27, circMAP3K13, and TSPEAR-AS2, respectively.miRNAs
In GC, miRNAs regulate gene expression by binding to the 3′untranslated region (3′UTR) of target mRNAs, leading to mRNA degradation or blocking ribosomal translation. Multiple miRNAs (e.g., miR-27, miR-195-5p, miR-124) have been identified as Influencing factors targeting oncogenic pathways such as EMT as well as Wnt/β-catenin signaling pathway in GC (57, 58). These findings highlight the critical regulatory roles of miRNAs in GC pathogenesis and their potential as therapeutic targets.
lncRNAs
The human genome encodes approximately 15,000 lncRNAs characterized by their remarkably diverse mechanisms of action. These regulatory molecules modulate epigenetic modifications through complex interactions suppressing or promoting gastric tumorigenesis (59). For instance, lncRNA TSPEAR-AS2 maintains the stemness of GC stem cells by regulating the miR-15a-5p/CCND1 axis (60). LncRNA BASP1-AS1 mediates histone H3K14 lactylation confering oxaliplatin resistance in GC (61). Despite these advances, significant knowledge gaps remain regarding the precise regulatory mechanisms that lncRNAs employ in GC.
circRNAs
CircRNAs are single-stranded, covalently closed non-coding RNAs produced by back-splicing. They function as miRNA sponges (ceRNAs), modulate protein activity and transcription, and can sometimes be translated into peptides (62). CircRNAs influence GC progression and offer potential as diagnostic markers or therapeutic targets. Such as circMAP3K13 enhances pyroptosis and reduces tumorigenicity and metastasis, circSRPK1 mediates GC progression by interacting with hnRNP A2B1 to regulate RON mRNA alternative splicing (63).
Summary and future perspectives
In current ncRNA research, systematically characterize functionally significant RNA molecules remains a central challenge. Furthermore, ncRNAs form intricate regulatory networks, for which comprehensive understanding remains limited, like lncRNA interact with various histone modification factors to regulate GC development (64, 65). Critical barriers such as low cross-species homology, tumor heterogeneity, and inefficient in vivo delivery further impede clinical translation.
To address these challenges, emerging technologies and strategies are advancing the field. Single-cell and spatial transcriptomics enable precise resolution of ncRNA expression dynamics within tissue microenvironments, while artificial intelligence and large language models offer novel computational frameworks for deciphering ncRNA regulatory networks. Clinically, the exceptional stability of ncRNAs in bodily fluids positions them as promising biomarkers.
RNA modifications
RNA modifications play pivotal roles in GC progression by dynamically regulating RNA stability, splicing, and translational efficiency. RNA modification is coordinately regulated by methyltransferases (“Writers”), demethylases (“Erasers”), and binding proteins (“Readers”), collectively governing diverse malignant behaviors in GC (66–68). Research on m6A modification has dominated the field, whereas progress in understanding many other RNA modifications has lagged behind (Figure 4).
The m6A Modification: a representative example of RNA modifications.
Illustration of mRNA modification process involving "writer," "reader," and "eraser" affecting mRNA with m6A modification. Surrounding boxes show related processes: growth, proliferation, apoptosis, immunotherapy, self-renewal, and metastasis.The m6A RNA methylation
The m6A writer METTL3 acts as an oncogene by stabilizing STAT5A and DEK mRNAs, thereby promoting GC progression (69–71), while METTL14-mediated m6A modification suppresses GC progression by regulating miR-30c-2-3p/AKT1S1 axis or lnc-PLCB1/DDX21 axis (72, 73). And METTL16 promotes GC via m6A-modification on FDX1 mRNA (74). Meanwhile reader diversify m6A-mediated phenotypes: YTHDF1 enhances USP14 translation to accelerate tumor growth, and YTHDF2 maintains cancer stemness by regulating ONECUT2 degradation, leading to oxaliplatin resistance (75, 76). Reader hnRNPA2B1 contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC (77). IGF2BP2-meidated m6A of CSF2 in reprogramming mesenchymal stem cells (MSCs), which presents a promising therapeutic target for GC (78). Eraser ALKBH5 suppresses GC by suppressing PI3K/Akt/mTOR signaling through PKMYT1/WRAP53 m6A demethylation yet promotes GC by activating JAK1 signaling via JAK1 demethylation (79–81). Additionally FTO facilitates metastasis by demethylating m6A from caveolin-1 and circFAM192A (82, 83). This regulatory complexity reveals the therapeutic potential of targeting specific m6A regulators in GC.
Other RNA methylations
The m7G modification, driven by the METTL1/WDR4 complex, promotes GC progression through enhancing oncogenic tRNA expression and facilitating the translation of oxidative phosphorylation-related genes, thereby accelerating metabolic reprogramming (84). Clinically, prognostic signatures based on m7G-associated lncRNAs show significant value in predicting patient survival and immunotherapy response (85, 86). Similarly, m5C modifications mediated by writers such as NSUN2 contribute to gastric carcinogenesis, with PTEN mRNA m5C modification playing a key role in progression (87). Elevated m5C levels enhance tumor cell invasiveness, highlighting its potential as a therapeutic target (88, 89).
Other RNA modifications
Upregulation of NAT10 by H. pylori infection promotes gastric tumorigenesis through ac4C-mediated stabilization of the oncogenic transcripts MDM2 and HK2 (90, 91). Additionally, NAT10 enhances the hypoxia tolerance of GC cells by mediating ac4C modification on SEPT9 mRNA, which activates the HIF-1 pathway and glycolytic reprogramming. Combining Apatinib with ac4C inhibition presents a promising strategy to overcome resistance to anti-angiogenic therapy (92, 93).
Summary and future perspectives
The “Writer-Eraser-Reader” network of RNA modifications presents a rich source of biomarkers and therapeutic targets. When evaluating their merit as biomarkers, the key regulators themselves often show the most immediate promise due to their druggable nature and measurable expression changes. For instance, the overexpression of the writer METTL3 and the reader YTHDF1 consistently correlates with poor survival and advanced disease stage, making them strong prognostic biomarkers (69, 75). The eraser FTO is another key player, whose upregulation promotes metastasis and could serve as both a prognostic marker and a therapeutic target (82, 83). The past 6 years have been pivotal in moving from cataloging these modifications to understanding their functional circuits. The current challenge is no longer just discovery but the development of high-throughput methods for absolute quantification of modifications like m6A in clinical samples. We anticipate that in the near future, panels combining the expression levels of key regulators (e.g., METTL3, YTHDF1, FTO) with specific modification signatures on oncogenic transcripts will provide powerful tools for GC diagnosis and subtyping.
Clinical translation and future perspectivesIntegrated epigenetic networks and biomarker potential
Emerging evidence reveals that DNA methylation and histone modifications frequently co-occur, forming interconnected epigenetic networks that mutually reinforce regulatory outcomes through cell context-dependent molecular interactions (94). This crosstalk is exemplified in GC cell line AGS, where H3K27me3-marked promoter regions consistently exhibit DNA hypermethylation, suggesting the potential for combined epigenetic targeting strategies (95). The development of diagnostic models incorporating both DNA methylation and histone modification profiles in premalignant lesions holds particular promise (96).
CircRNAs have emerged as attractive biomarker candidates due to their unique covalently closed circular structure, which confers exceptional resistance to exonuclease and RNase R degradation while enabling stage-specific expression patterns across diverse tissues (97). Their remarkable stability in biological fluids makes them ideal for liquid biopsy applications.
Epigenetic-based strategies for GC management have demonstrated remarkable clinical potential across multiple applications. For early detection, China’s Expert Consensus on Early Gastric Cancer Screening Technologies has endorsed RNF180/Septin9 methylation assays as viable screening tools, with NMPA-approved commercial kits now available for high-risk populations (27). Additional promising non-invasive biomarkers including MINT31 and APC methylation are under active investigation (98, 99). Prognostically, hypermethylation of SPG20 and FBN1 has shown significant correlation with poor clinical outcomes, while CPNE1 methylation status serves as a predictive biomarker for chemotherapy response (28).
Epigenetic-targeted therapies in GC
Several epigenetic inhibitors have shown promise in preclinical and clinical studies for GC. DNMT inhibitors (e.g., azacitidine) and HDAC inhibitors (e.g., vorinostat, chidamide) are being evaluated for their ability to reverse aberrant methylation and acetylation patterns (100–102). Additionally, inhibitors targeting specific epigenetic readers (e.g., BET inhibitors) and writers (e.g., METTL3 inhibitors) are under investigation. For example, STM2457 can precisely target METTL3, minimizing effects on other methyltransferases (103). As the first METTL3 inhibitor to enter clinical evaluation (NCT05584111), STC-15 demonstrates transformative potential in translating epitranscriptomic discoveries into therapeutic applications (104). These inhibitors have demonstrated significant efficacy in suppressing tumor cell proliferation, migration, and invasion, particularly in GC.
In therapeutic development, current epigenetic therapies need optimization through precision delivery systems such as METTL3 siRNA-loaded nanoparticles, rational combination strategies like HDAC inhibitors with immunotherapy, and innovative approaches including CRISPR-dCas9-mediated targeted demethylation to address tumor heterogeneity (105, 106). A new research shows an innovative diagnostic and therapeutic 808 nm NIR laser irradiation-triggered engineered microbe that establishes an efficient delivery platform for DNMT1 inhibitors and iMXene, activating epigenetic immunity and paving the way for the broad application of epigenetic regulation in solid tumor treatment (107).
The translation of epigenetic biomarkers requires rigorous clinical validation. Future research should prioritize the identification and validation of biomarkers with well-defined mechanisms and clear clinical relevance. Successful clinical implementation will depend on multidisciplinary collaboration across molecular biology, materials science and bioinformatics to establish GC-specific epigenetic databases and advance single-cell epigenomic technologies, while developing ethical guidelines for emerging technologies like epigenetic editing. The future of GC epigenetics lies in developing clinically validated high-sensitivity detection systems, implementing multi-omics-guided precision therapy, and building cross-disciplinary innovation ecosystems. As the field transitions from mechanistic discovery to clinical implementation, these advances promise to revolutionize early detection and personalized treatment, ultimately achieving precision medicine for GC patients through sustained collaboration across academia, clinical practice and industry. Advances in ChIP, CUT&Tag, and high-resolution sequencing are profoundly transforming GC epigenetics. Moving forward, integrating multi-omics data across molecular, cellular, and tissue levels will systematically uncover the core functions of epigenetic regulation, translating these insights into clinical predictive models and precision therapies.
Future directions should focus on: (1) elucidating synergistic epigenetic mechanisms to refine diagnostic models; (2) developing real-time liquid biopsy platforms for treatment monitoring and recurrence surveillance; (3) implementing precision medicine approaches through integrated epigenetic profiling. These advances will likely transform GC management from reactive treatment to proactive interception.
Conclusion
As summarized in Table 1, the past 6 years have yielded a wealth of candidate epigenetic biomarkers for GC. However, it is clear that not all are created equal. From a translational perspective, DNA methylation markers (particularly RNF180/Septin9) currently hold the most immediate promise for early detection, as evidenced by their regulatory approval and inclusion in clinical guidelines. Non-coding RNAs like miR-21 offer robustness due to their high abundance, while key RNA modification regulators (e.g., METTL3) represent compelling targets for both therapy and companion diagnostics (108, 109). Despite this progress, the field’s primary challenge is no longer discovery but validation and integration. Current liquid biopsy approaches based on single markers still lack the sensitivity for reliable early-stage detection. Therefore, we argue that the most constructive path forward is the development of integrated multi-omics liquid biopsy panels that combine the best-in-class epigenetic markers (e.g., RNF180 methylation) with other analyte types (e.g., fragmentomics, proteomics) to achieve the necessary diagnostic performance.
Representative epigenetic biomarkers in gastric cancer.
RZ: Supervision, Writing – review and editing, Software, Investigation, Methodology, Formal Analysis, Writing – original draft, Resources, Validation, Funding acquisition, Project administration, Data curation, Visualization, Conceptualization. JC: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review and editing.
Acknowledgements
The authors appreciate the administrative support from The Third Affiliated Hospital of Sun Yat-sen University.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Edited by:Li-Juan Zhao, Zhengzhou University, China
Reviewed by:Anupam Chatterjee, Royal Global University, India
Abdullah Mamun, University of Mississippi, United States
ReferencesJassimARahrmannEPSimonsBDGilbertsonRJ. Cancers make their own luck: theories of cancer origins. Nat Reviews Cancer (2023) 23(10):710–24. 10.1038/s41568-023-00602-537488363JonesPA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Reviews Genet (2012) 13(7):484–92. 10.1038/nrg323022641018ZhaoSAllisCDWangGG. The language of chromatin modification in human cancers. Nat Reviews Cancer (2021) 21(7):413–30. 10.1038/s41568-021-00357-x34002060LanQLiuPYHaaseJBellJLHüttelmaierSLiuT. The critical role of rna M(6)a methylation in cancer. Cancer Research (2019) 79(7):1285–92. 10.1158/0008-5472.Can-18-296530894375SmythECNilssonMGrabschHIvan GriekenNCLordickF. Gastric cancer. Lancet (London, England) (2020) 396(10251):635–48. 10.1016/s0140-6736(20)31288-532861308SiegelRLGiaquintoANJemalA. Cancer statistics, 2024. CA: A Cancer Journal Clinicians (2024) 74(1):12–49. 10.3322/caac.2182038230766HeFWangSZhengRGuJZengHSunKTrends of gastric cancer burdens attributable to risk factors in China from 2000 to 2050. The Lancet Regional Health West Pac (2024) 44:101003. 10.1016/j.lanwpc.2023.10100338269331SkvortsovaKIovinoNBogdanovićO. Functions and mechanisms of epigenetic inheritance in animals. Nat Reviews Mol Cell Biology (2018) 19(12):774–90. 10.1038/s41580-018-0074-230425324MatsusakaKFunataSFukayamaMKanedaA. DNA methylation in gastric cancer, related to Helicobacter pylori and epstein-barr virus. World Journal Gastroenterology (2014) 20(14):3916–26. 10.3748/wjg.v20.i14.391624744581KangGHShimYHJungHYKimWHRoJYRhyuMG. Cpg island methylation in premalignant stages of gastric carcinoma. Cancer Research (2001) 61(7):2847–51.11306456SepulvedaJLGutierrez-PajaresJLLunaAYaoYTobiasJWThomasSHigh-definition cpg methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing. Mod Pathology : An Official Journal United States Can Acad Pathol Inc (2016) 29(2):182–93. 10.1038/modpathol.2015.14426769141NiwaTTsukamotoTToyodaTMoriATanakaHMaekitaTInflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Research (2010) 70(4):1430–40. 10.1158/0008-5472.Can-09-275520124475ShijimayaTTaharaTShimogamaTYamazakiJKobayashiSNakamuraNGastric microbiome composition accompanied with the Helicobacter pylori related DNA methylation anomaly. Epigenomics (2024) 16(21-22):1329–36. 10.1080/17501911.2024.241880339492780NiwaTToyodaTTsukamotoTMoriATatematsuMUshijimaT. Prevention of helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prevention Research (2013) 6(4):263–70. 10.1158/1940-6207.Capr-12-036923559452MaekitaTNakazawaKMiharaMNakajimaTYanaokaKIguchiMHigh levels of aberrant DNA methylation in helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Research : An Official Journal Am Assoc Cancer Res (2006) 12(3 Pt 1):989–95. 10.1158/1078-0432.Ccr-05-209616467114BessèdeEMégraudF. Microbiota and gastric cancer. Semin Cancer Biology (2022) 86(Pt 3):11–7. 10.1016/j.semcancer.2022.05.00135533800UshikuTChongJMUozakiHHinoRChangMSSudoMP73 gene promoter methylation in epstein-barr virus-associated gastric carcinoma. Int Journal Cancer (2007) 120(1):60–6. 10.1002/ijc.2227517058198MatsusakaKKanedaANagaeGUshikuTKikuchiYHinoRClassification of epstein-barr virus-positive gastric cancers by definition of DNA methylation epigenotypes. Cancer Research (2011) 71(23):7187–97. 10.1158/0008-5472.Can-11-134921990320XuWHuangYYangZHuYShuXXieCHelicobacter pylori promotes gastric epithelial cell survival through the Plk1/Pi3k/Akt pathway. OncoTargets Therapy (2018) 11:5703–13. 10.2147/ott.S16474930254463LiuWPengZZZhangTLiaoKLiJ. Burden, trends, driving factors, and predictions of gastric cancer: a cross-national comparative analysis of China, Japan, and South Korea. BMC Cancer (2025) 25(1):1669. 10.1186/s12885-025-15009-841163138QianZBaiWLiJRaoXHuangGZhangXGut microbiome-mediated epigenetic modifications in gastric cancer: a comprehensive multiomics analysis. Front Cellular Infection Microbiology (2025) 15:1585881. 10.3389/fcimb.2025.158588141181327BaekSJKimMBaeDHKimJHKimHJHanMEIntegrated epigenomic analyses of enhancer as well as promoter regions in gastric cancer. Oncotarget (2016) 7(18):25620–31. 10.18632/oncotarget.823927016420MaruyamaSImamuraYToihataTHaraguchiITakamatsuMYamashitaMFoxp3+/Cd8+ ratio associated with aggressive behavior in Runx3-Methylated diffuse esophagogastric junction tumor. Cancer Science (2025) 116(1):178–91. 10.1111/cas.1637339440906NakamuraKSuehiroYHamabeKGotoAHashimotoSKunimuneYA novel index including age, sex, htert, and methylated Runx3 is useful for diagnosing early gastric cancer. Oncology (2025) 103(4):320–6. 10.1159/00054117339236692KangYHLeeHSKimWH. Promoter methylation and silencing of pten in gastric carcinoma. Lab Investigation; a Journal Technical Methods Pathology (2002) 82(3):285–91. 10.1038/labinvest.378042211896207SeoSYYounSHBaeJHLeeSHLeeSY. Detection and characterization of methylated circulating tumor DNA in gastric cancer. Int Journal Molecular Sciences (2024) 25(13):7377. 10.3390/ijms2513737739000483NaganoSKurokawaYHagiTYoshiokaRTakahashiTSaitoTExtensive methylation analysis of circulating tumor DNA in plasma of patients with gastric cancer. Scientific Reports (2024) 14(1):30739. 10.1038/s41598-024-79252-y39730450QiJHongBWangSWangJFangJSunRPlasma cell-free DNA methylome-based liquid biopsy for accurate gastric cancer detection. Cancer Science (2024) 115(10):3426–38. 10.1111/cas.1628439038922LinBJiaoZDongSYanWJiangJDuYWhole-genome methylation profiling of extracellular vesicle DNA in gastric cancer identifies intercellular communication features. Nat Communications (2025) 16(1):8084. 10.1038/s41467-025-63435-w40883299TangWZhuZWangZLiGLinQCaiSDNA methylation profiles predicting response to Anti-Pd-1-Based treatment in patients with advanced gastric cancer. BMC Medicine (2025) 23(1):529. 10.1186/s12916-025-04357-841034874JuJZhangHLinMYanZAnLCaoZThe alanyl-trna synthetase Aars1 moonlights as a lactyltransferase to promote Yap signaling in gastric cancer. The J Clinical Investigation (2024) 134(10):e174587. 10.1172/jci17458738512451YangHZouXYangSZhangALiNMaZ. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front Immunology (2023) 14:1149989. 10.3389/fimmu.2023.114998936936929SunXDongHSuRChenJLiWYinSLactylation-related gene signature accurately predicts prognosis and immunotherapy response in gastric cancer. Front Oncology (2024) 14:1485580. 10.3389/fonc.2024.148558039669362TsukiharaSAkiyamaYShimadaSHatanoMIgarashiYTaniaiTDelactylase effects of Sirt1 on a positive feedback loop involving the H19-Glycolysis-Histone lactylation in gastric cancer. Oncogene (2025) 44(11):724–38. 10.1038/s41388-024-03243-639658647ZhaoYJiangJZhouPDengKLiuZYangMH3k18 lactylation-mediated Vcam1 expression promotes gastric cancer progression and metastasis via Akt-Mtor-Cxcl1 axis. Biochem Pharmacology (2024) 222:116120. 10.1016/j.bcp.2024.11612038461905XiaGSchneider-StockRDiestelAHaboldCKruegerSRoessnerAHelicobacter pylori regulates P21(Waf1) by histone H4 acetylation. Biochem Biophysical Research Communications (2008) 369(2):526–31. 10.1016/j.bbrc.2008.02.07318302936ParkYSJinMYKimYJYookJHKimBSJangSJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surgical Oncology (2008) 15(7):1968–76. 10.1245/s10434-008-9927-918470569WisnieskiFLealMFCalcagnoDQSantosLCGigekCOChenESBmp8b is a tumor suppressor gene regulated by histone acetylation in gastric cancer. J Cellular Biochemistry (2017) 118(4):869–77. 10.1002/jcb.2576627748538WeichertWRöskeAGekelerVBeckersTEbertMPProssMAssociation of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. The Lancet Oncol (2008) 9(2):139–48. 10.1016/s1470-2045(08)70004-418207460LinYJingXChenZPanXXuDYuXHistone deacetylase-mediated tumor microenvironment characteristics and synergistic immunotherapy in gastric cancer. Theranostics (2023) 13(13):4574–600. 10.7150/thno.8692837649598LeeSWParkDYKimMYKangC. Synergistic triad epistasis of epigenetic H3k27me modifier genes, Ezh2, Kdm6a, and Kdm6b, in gastric cancer susceptibility. Gastric Cancer Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (2019) 22(3):640–4. 10.1007/s10120-018-0888-930374835ShenDDPangJRBiYPZhaoLFLiYRZhaoLJLsd1 deletion decreases exosomal Pd-L1 and restores T-Cell response in gastric cancer. Mol Cancer (2022) 21(1):75. 10.1186/s12943-022-01557-135296335WuJChaiHXuXYuJGuY. Histone methyltransferase Setd1a interacts with Hif1α to enhance glycolysis and promote cancer progression in gastric cancer. Mol Oncology (2020) 14(6):1397–409. 10.1002/1878-0261.1268932291851MurakamiY. Phosphorylation of repressive histone code readers by casein kinase 2 plays diverse roles in heterochromatin regulation. J Biochemistry (2019) 166(1):3–6. 10.1093/jb/mvz04531198932YangTTCaoNZhangHHWeiJBSongXXYiDMHelicobacter pylori infection-induced H3ser10 phosphorylation in stepwise gastric carcinogenesis and its clinical implications. Helicobacter (2018) 23(3):e12486. 10.1111/hel.1248629656498TakahashiHMuraiYTsuneyamaKNomotoKOkadaEFujitaHOverexpression of phosphorylated histone H3 is an indicator of poor prognosis in gastric adenocarcinoma patients. Appl Immunohistochemistry and Molecular Morphology : AIMM (2006) 14(3):296–302. 10.1097/00129039-200609000-0000716932020WangJQiuZWuY. Ubiquitin regulation: the histone modifying enzyme's story. Cells (2018) 7(9). 10.3390/cells709011830150556SwatekKNKomanderD. Ubiquitin modifications. Cell Research (2016) 26(4):399–422. 10.1038/cr.2016.3927012465WangZJYangJLWangYPLouJYChenJLiuCDecreased histone H2b monoubiquitination in malignant gastric carcinoma. World Journal Gastroenterology (2013) 19(44):8099–107. 10.3748/wjg.v19.i44.809924307806KlemmSLShiponyZGreenleafWJ. Chromatin accessibility and the regulatory epigenome. Nat Reviews Genet (2019) 20(4):207–20. 10.1038/s41576-018-0089-830675018GuYZhangPWangJLinCLiuHLiHSomatic Arid1a mutation stratifies patients with gastric cancer to Pd-1 blockade and adjuvant chemotherapy. Cancer Immunology, Immunotherapy : CII (2023) 72(5):1199–208. 10.1007/s00262-022-03326-x36369379MaFRenMLiZTangYSunXWangYArid1a is a coactivator of Stat5 that contributes to Cd8(+) T cell dysfunction and Anti-Pd-1 resistance in gastric cancer. Pharmacol Research (2024) 210:107499. 10.1016/j.phrs.2024.10749939549895WuJZhouZLiJLiuHZhangHZhangJChd4 promotes acquired chemoresistance and tumor progression by activating the mek/erk axis. Drug Resistance Updates : Reviews Commentaries Antimicrobial Anticancer Chemotherapy (2023) 66:100913. 10.1016/j.drup.2022.10091336603431HashimotoTKurokawaYWadaNTakahashiTMiyazakiYTanakaKClinical significance of chromatin remodeling factor Chd5 expression in gastric cancer. Oncol Letters (2020) 19(1):1066–73. 10.3892/ol.2019.1113831897220ZhangJLiJYangSTangXWangCLinJDevelopment and validation of an Arid1a-Related immune genes risk model in evaluating prognosis and immune therapeutic efficacy for gastric cancer patients: a translational study. Front Immunology (2025) 16:1541491. 10.3389/fimmu.2025.154149140406134HolochDMoazedD. Rna-mediated epigenetic regulation of gene expression. Nat Reviews Genet (2015) 16(2):71–84. 10.1038/nrg386325554358LiuLTianYCMaoGZhangYGHanL. Mir-675 is frequently overexpressed in gastric cancer and enhances cell proliferation and invasion via targeting a potent anti-tumor gene Pitx1. Cell Signalling (2019) 62:109352. 10.1016/j.cellsig.2019.10935231260797YanJZhangYSheQLiXPengLWangXLong noncoding rna H19/Mir-675 axis promotes gastric cancer via fadd/caspase 8/Caspase 3 signaling pathway. Cell Physiology Biochemistry : International Journal Experimental Cellular Physiology, Biochemistry, Pharmacology (2017) 42(6):2364–76. 10.1159/00048002828848149ChuaPJLimJPGuoTTKhannaPHuQBayBHY-Box binding Protein-1 and Stat3 independently regulate atp-binding cassette transporters in the chemoresistance of gastric cancer cells. Int Journal Oncology (2018) 53(6):2579–89. 10.3892/ijo.2018.455730221675HanHWangSMengJLyuGDingGHuYLong noncoding rna Part1 restrains aggressive gastric cancer through the epigenetic silencing of pdgfb via the plzf-mediated recruitment of Ezh2. Oncogene (2020) 39(42):6513–28. 10.1038/s41388-020-01442-532901105LiQWangYChenLShenYZhangSYueDLncrna Tspear-As2 maintains the stemness of gastric cancer stem cells by regulating the Mir-15a-5p/Ccnd1 axis. Biomolecules (2025) 15(9):1227. 10.3390/biom1509122741008534ZhaoYLiuWDengKChenYZhouPLiuCLncrna Basp1-As1 drives Pcbp2 K115 lactylation to suppress ferroptosis and confer oxaliplatin resistance in gastric cancer. Free Radical Biology and Medicine (2025) 240:717–34. 10.1016/j.freeradbiomed.2025.09.00240914325DuKZhangXQinYMaHBingCDengSMap3k13-232aa encoded by Circmap3k13 enhances cisplatin-induced pyroptosis by directly binding to Ikkα in gastric adenocarcinoma. Cell Death and Disease (2025) 16(1):667. 10.1038/s41419-025-07991-540890114YuSChenMJiangKChenCLiangJZhengJCircsrpk1 mediated by the exon junction complex promotes gastric cancer progression by interacting with hnrnp A2b1 to regulate ron mrna alternative splicing. Cancer Letters (2025) 629:217879. 10.1016/j.canlet.2025.21787940532817LianYYanCLianYYangRChenQMaDLong intergenic non-protein-coding rna 01446 facilitates the proliferation and metastasis of gastric cancer cells through interacting with the histone lysine-specific demethylase Lsd1. Cell Death and Disease (2020) 11(7):522. 10.1038/s41419-020-2729-032651355PanYFangYXieMLiuYYuTWuXLinc00675 suppresses cell proliferation and migration via downregulating the H3k4me2 level at the Spry4 promoter in gastric cancer. Mol Therapy Nucleic Acids (2020) 22:766–78. 10.1016/j.omtn.2020.09.03833230474SangLSunLWangAZhangHYuanY. The N6-Methyladenosine features of mrna and aberrant expression of M6a modified genes in gastric cancer and their potential impact on the risk and prognosis. Front Genetics (2020) 11:561566. 10.3389/fgene.2020.56156633329697XuPLiuKHuangSLvJYanZGeHN(6)-Methyladenosine-Modified Mib1 promotes stemness properties and peritoneal metastasis of gastric cancer cells by ubiquitinating Ddx3x. Gastric Cancer : Official Journal Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc (2024) 27(2):275–91. 10.1007/s10120-023-01463-538252226XuPYangJChenZZhangXXiaYWangSN6-Methyladenosine modification of cenpf mrna facilitates gastric cancer metastasis via regulating fak nuclear export. Cancer Communications (London, England) (2023) 43(6):685–705. 10.1002/cac2.1244337256823WangQChenCDingQZhaoYWangZChenJMettl3-Mediated M(6)a modification of hdgf mrna promotes gastric cancer progression and has prognostic significance. Gut (2020) 69(7):1193–205. 10.1136/gutjnl-2019-31963931582403ZangYTianZWangDLiYZhangWMaCMettl3-Mediated N(6)-Methyladenosine modification of Stat5a promotes gastric cancer progression by regulating Klf4. Oncogene (2024) 43(30):2338–54. 10.1038/s41388-024-03085-238879589LiuYZhaiEChenJQianYZhaoRMaYM(6) a-Mediated regulation of Pbx1-Gch1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels. Cancer Communications (London, England) (2022) 42(4):327–44. 10.1002/cac2.1228135261206FanHNChenZYChenXYChenMYiYCZhuJSMettl14-Mediated M(6)a modification of Circorc5 suppresses gastric cancer progression by regulating Mir-30c-2-3p/Akt1s1 axis. Mol Cancer (2022) 21(1):51. 10.1186/s12943-022-01521-z35164771ChangMCuiXSunQWangYLiuJSunZLnc-Plcb1 is stabilized by Mettl14 induced M6a modification and inhibits Helicobacter pylori mediated gastric cancer by destabilizing Ddx21. Cancer Letters (2024) 588:216746. 10.1016/j.canlet.2024.21674638387756SunLZhangYYangBSunSZhangPLuoZLactylation of Mettl16 promotes cuproptosis via M(6)a-Modification on Fdx1 mrna in gastric cancer. Nat Communications (2023) 14(1):6523. 10.1038/s41467-023-42025-837863889ChenXYLiangRYiYCFanHNChenMZhangJThe M(6)a reader Ythdf1 facilitates the tumorigenesis and metastasis of gastric cancer via Usp14 translation in an M(6)a-Dependent manner. Front Cell Developmental Biology (2021) 9:647702. 10.3389/fcell.2021.64770233791305FanXHanFWangHShuZQiuBZengFYthdf2-Mediated M(6)a modification of Onecut2 promotes stemness and oxaliplatin resistance in gastric cancer through transcriptionally activating tfpi. Drug Resistance Updates : Reviews Commentaries Antimicrobial Anticancer Chemotherapy (2025) 79:101200. 10.1016/j.drup.2024.10120039823826WangJZhangJLiuHMengLGaoXZhaoYN6-Methyladenosine reader Hnrnpa2b1 recognizes and stabilizes Neat1 to confer chemoresistance in gastric cancer. Cancer Communications (London, England) (2024) 44(4):469–90. 10.1002/cac2.1253438512764JiRWuCYaoJXuJLinJGuHIgf2bp2-Meidated M(6)a modification of Csf2 reprograms msc to promote gastric cancer progression. Cell Death and Disease (2023) 14(10):693. 10.1038/s41419-023-06163-737865637HuYGongCLiZLiuJChenYHuangYDemethylase Alkbh5 suppresses invasion of gastric cancer via Pkmyt1 M6a modification. Mol Cancer (2022) 21(1):34. 10.1186/s12943-022-01522-y35114989ZhengZLinFZhaoBChenGWeiCChenXAlkbh5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped Wrap53 rna isoforms in an M6a-Dependent manner. Mol Cancer (2025) 24(1):19. 10.1186/s12943-024-02223-439815301FangYWuXGuYShiRYuTPanYLinc00659 cooperated with Alkbh5 to accelerate gastric cancer progression by stabilising Jak1 mrna in an M(6) a-Ythdf2-Dependent manner. Clin Translational Medicine (2023) 13(3):e1205. 10.1002/ctm2.120536864711ZhouYWangQDengHXuBZhouYLiuJN6-Methyladenosine demethylase fto promotes growth and metastasis of gastric cancer via M(6)a modification of Caveolin-1 and metabolic regulation of mitochondrial dynamics. Cell Death and Disease (2022) 13(1):72. 10.1038/s41419-022-04503-735064107WuXFangYGuYShenHXuYXuTFat mass and obesity-associated protein (fto) mediated M(6)a modification of Circfam192a promoted gastric cancer proliferation by suppressing Slc7a5 decay. Mol Biomedicine (2024) 5(1):11. 10.1186/s43556-024-00172-438556586XuXHuangZHanHYuZYeLZhaoZN(7)-Methylguanosine trna modification promotes gastric cancer progression by activating Sdhaf4-Dependent mitochondrial oxidative phosphorylation. Cancer Letters (2025) 615:217566. 10.1016/j.canlet.2025.21756639965707ZhaoBFangFLiaoYChenYWangFMaYNovel M7g-Related lncrna signature for predicting overall survival in patients with gastric cancer. BMC Bioinformatics (2023) 24(1):100. 10.1186/s12859-023-05228-w36935487MaMLiJZengZZhengZKangW. Integrated analysis from multicentre studies identities M7g-Related lncrna-derived molecular subtypes and risk stratification systems for gastric cancer. Front Immunology (2023) 14:1096488. 10.3389/fimmu.2023.109648836936957ZhaoGLiuRGeLQiDWuQLinZNono regulates M(5)C modification and alternative splicing of pten mrnas to drive gastric cancer progression. J Experimental and Clinical Cancer Research : CR (2025) 44(1):81. 10.1186/s13046-024-03260-z40033337LiYXiaYJiangTChenZShenYLinJLong noncoding rna Diaph2-As1 promotes neural invasion of gastric cancer via stabilizing Nsun2 to enhance the M5c modification of Ntn1. Cell Death and Disease (2023) 14(4):260. 10.1038/s41419-023-05781-537037818LiuKXuPLvJGeHYanZHuangSPeritoneal high-fat environment promotes peritoneal metastasis of gastric cancer cells through activation of Nsun2-Mediated Orai2 M5c modification. Oncogene (2023) 42(24):1980–93. 10.1038/s41388-023-02707-537130916DengMZhangLZhengWChenJDuNLiMHelicobacter pylori-induced Nat10 stabilizes Mdm2 mrna via rna acetylation to facilitate gastric cancer progression. J Experimental and Clinical Cancer Research : CR (2023) 42(1):9. 10.1186/s13046-022-02586-w36609449WangQLiMChenCXuLFuYXuJGlucose homeostasis controls N-Acetyltransferase 10-Mediated Ac4c modification of Hk2 to drive gastric tumorigenesis. Theranostics (2025) 15(6):2428–50. 10.7150/thno.10431039990211YangQLeiXHeJPengYZhangYLingRN4-Acetylcytidine drives glycolysis addiction in gastric cancer via Nat10/Sept9/Hif-1α positive feedback loop. Adv Science (Weinheim, Baden-Wurttemberg, Germany) (2023) 10(23):e2300898. 10.1002/advs.20230089837328448ChenCWangZLinQLiMXuLFuYNat10 promotes gastric cancer liver metastasis by modulation of M2 macrophage polarization and metastatic tumor cell hepatic adhesion. Adv Science (Weinheim, Baden-Wurttemberg, Germany) (2025) 12(15):e2410263. 10.1002/advs.20241026339985269SogutluFPekerbasMBoztasGBayramEPariltayECoguluOThe anticancer potential of Origanum onites L. in gastric cancer through epigenetic alterations. BMC Complementary Medicine Therapies (2025) 25(1):220. 10.1186/s12906-025-04942-740604718GaoFJiGGaoZHanXYeMYuanZDirect chip-bisulfite sequencing reveals a role of H3k27me3 mediating aberrant hypermethylation of promoter cpg islands in cancer cells. Genomics (2014) 103(2-3):204–10. 10.1016/j.ygeno.2013.12.00624407023PadmanabhanNUshijimaTTanP. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Reviews Gastroenterol and Hepatology (2017) 14(8):467–78. 10.1038/nrgastro.2017.5328513632NieYGaoXCaiXWuZLiangQXuGCombining methylated Septin9 and Rnf180 plasma markers for diagnosis and early detection of gastric cancer. Cancer Communications (London, England) (2023) 43(11):1275–9. 10.1002/cac2.1247837584087HideuraESuehiroYNishikawaJShutoTFujimuraHItoSBlood free-circulating DNA testing of methylated Runx3 is useful for diagnosing early gastric cancer. Cancers (2020) 12(4). 10.3390/cancers1204078932224873LiGPingMGuoJWangJ. Comprehensive analysis of Cpne1 predicts prognosis and drug resistance in gastric adenocarcinoma. Am Journal Translational Research (2024) 16(6):2233–47. 10.62347/niyr209439006290MomparlerRL. Pharmacology of 5-Aza-2'-Deoxycytidine (decitabine). Semin Hematology (2005) 42(3 Suppl. 2):S9–16. 10.1053/j.seminhematol.2005.05.00216015507DaiWLiuSZhangJPeiMXiaoYLiJVorinostat triggers Mir-769-5p/3p-Mediated suppression of proliferation and induces apoptosis via the Stat3-Igf1r-Hdac3 complex in human gastric cancer. Cancer Letters (2021) 521:196–209. 10.1016/j.canlet.2021.09.00134481934SinghAChangTYKaurNHsuKCYenYLinTECap rigidification of Ms-275 and chidamide leads to enhanced antiproliferative effects mediated through Hdac1, 2 and tubulin polymerization inhibition. Eur Journal Medicinal Chemistry (2021) 215:113169. 10.1016/j.ejmech.2021.11316933588178YankovaEBlackabyWAlbertellaMRakJDe BraekeleerETsagkogeorgaGSmall-molecule inhibition of Mettl3 as a strategy against myeloid leukaemia. Nature (2021) 593(7860):597–601. 10.1038/s41586-021-03536-w33902106RosenfeldYORauschOMcMahonJVasiliauskaiteLSaundersCSapetschnigA1373 Stc-15, an oral small molecule inhibitor of the rna methyltransferase Mettl3, inhibits tumour growth through activation of anti-cancer immune responses and synergises with immune checkpoint blockade. J ImmunoTherapy Cancer (2022) 10(Suppl. 2):A1427. 10.1136/jitc-2022-SITC2022.1373SukochevaOALiuJNeganovaMEBeerakaNMAleksandrovaYRManogaranPPerspectives of using microrna-loaded nanocarriers for epigenetic reprogramming of drug resistant colorectal cancers. Semin Cancer Biology (2022) 86(Pt 2):358–75. 10.1016/j.semcancer.2022.05.01235623562DavalosVEstellerM. Cancer epigenetics in clinical practice. CA: A Cancer Journal Clinicians (2023) 73(4):376–424. 10.3322/caac.2176536512337LouCLiYZhanRFangYZhangALiuYPhoto-triggered engineered microbes achieving dual epigenetic immunomodulation for gastric cancer. Biomaterials (2026) 325:123608. 10.1016/j.biomaterials.2025.12360840829506ZhangYLiuHLiWYuJLiJShenZCircrna_100269 is downregulated in gastric cancer and suppresses tumor cell growth by targeting Mir-630. Aging (2017) 9(6):1585–94. 10.18632/aging.10125428657541GlossaryGC