Gastric cancer (GC) remains a major cause of cancer-related mortality. Recent advances in high-throughput technologies have illuminated the role of epigenetic mechanisms in gene expression regulation. Epigenetic features contribute to molecular classification and define cancer-specific patterns. Helicobacter pylori (Hp) infection influences DNA methylation through its CagA protein or chronic inflammation, while Epstein-Barr virus (EBV) infection dysregulates DNA methyltransferases (DNMTs), leading to aggressive tumor behavior. Histone modifications also regulate oncogene activation and tumor suppressor gene silencing in GC. While histone methylation and acetylation are well-studied, other epigenetic alterations contribute to GC development and progression through complex interactions. Enzymes like Nicotinamide N-methyltransferase (NNMT) interact with methyltransferases to modify gene expression. Non-coding RNAs, including long non-coding RNAs (lncRNAs), circular RNAs, and miRNAs, act as epigenetic regulators in GC development, metastasis, and therapy resistance. Serum RNA molecules hold potential as non-invasive biomarkers for diagnosis, prognosis, and treatment. Gastric fluids offer valuable biomarkers for liquid biopsy. Clinical trials are evaluating next-generation epigenetic drugs, showing promising results. Approaches such as miRNA inhibitors and targeted nanoparticles are being developed to enhance treatment efficacy and overcome resistance. Epigenetic alterations regulate gene expression without altering DNA sequence. DNA methylation, histone modifications, and non-coding RNAs are key epigenetic mechanisms in GC. DNA methylation is crucial for gene regulation, with aberrant methylation in genes like DAPK, E-cadherin, and p16 linked to GC. Histone modifications, including methylation and acetylation, influence gene expression and tumor progression. Non-coding RNAs, such as miRNAs, lncRNAs, and circRNAs, regulate GC development and prognosis. Epigenetic changes are associated with GC subtypes, including CIMP and EBV-positive tumors. Epigenetic biomarkers, such as CDH1 and MLH1, are important for diagnosis and prognosis. Epigenetic therapies, including DNMT and EZH2 inhibitors, are being explored for GC treatment. Epigenetic modifications are also linked to immune evasion and resistance to immunotherapy. The interplay between epigenetics, metabolism, and the microbiome is critical for understanding GC progression. Epigenetic biomarkers, such as PD-L1 and PD-L2, are important for immunotherapy response prediction. Epigenetic therapies, including DNMT and EZH2 inhibitors, are being evaluated for their potential in GC treatment. Epigenetic modifications are also linked to immune evasion and resistance to immunotherapy. The role of epigenetics in GC is a promising area for developing novel diagnostic and therapeutic strategies.Gastric cancer (GC) remains a major cause of cancer-related mortality. Recent advances in high-throughput technologies have illuminated the role of epigenetic mechanisms in gene expression regulation. Epigenetic features contribute to molecular classification and define cancer-specific patterns. Helicobacter pylori (Hp) infection influences DNA methylation through its CagA protein or chronic inflammation, while Epstein-Barr virus (EBV) infection dysregulates DNA methyltransferases (DNMTs), leading to aggressive tumor behavior. Histone modifications also regulate oncogene activation and tumor suppressor gene silencing in GC. While histone methylation and acetylation are well-studied, other epigenetic alterations contribute to GC development and progression through complex interactions. Enzymes like Nicotinamide N-methyltransferase (NNMT) interact with methyltransferases to modify gene expression. Non-coding RNAs, including long non-coding RNAs (lncRNAs), circular RNAs, and miRNAs, act as epigenetic regulators in GC development, metastasis, and therapy resistance. Serum RNA molecules hold potential as non-invasive biomarkers for diagnosis, prognosis, and treatment. Gastric fluids offer valuable biomarkers for liquid biopsy. Clinical trials are evaluating next-generation epigenetic drugs, showing promising results. Approaches such as miRNA inhibitors and targeted nanoparticles are being developed to enhance treatment efficacy and overcome resistance. Epigenetic alterations regulate gene expression without altering DNA sequence. DNA methylation, histone modifications, and non-coding RNAs are key epigenetic mechanisms in GC. DNA methylation is crucial for gene regulation, with aberrant methylation in genes like DAPK, E-cadherin, and p16 linked to GC. Histone modifications, including methylation and acetylation, influence gene expression and tumor progression. Non-coding RNAs, such as miRNAs, lncRNAs, and circRNAs, regulate GC development and prognosis. Epigenetic changes are associated with GC subtypes, including CIMP and EBV-positive tumors. Epigenetic biomarkers, such as CDH1 and MLH1, are important for diagnosis and prognosis. Epigenetic therapies, including DNMT and EZH2 inhibitors, are being explored for GC treatment. Epigenetic modifications are also linked to immune evasion and resistance to immunotherapy. The interplay between epigenetics, metabolism, and the microbiome is critical for understanding GC progression. Epigenetic biomarkers, such as PD-L1 and PD-L2, are important for immunotherapy response prediction. Epigenetic therapies, including DNMT and EZH2 inhibitors, are being evaluated for their potential in GC treatment. Epigenetic modifications are also linked to immune evasion and resistance to immunotherapy. The role of epigenetics in GC is a promising area for developing novel diagnostic and therapeutic strategies.