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<p>Globally, gastric cancer (GC) ranks among the deadliest malignancies due to frequent late-stage detection, metastatic dissemination, and resistance to therapies. Emerging evidence highlights N⁶-methyladenosine (m⁶A) modification, orchestrated by methyltransferase-like 3 (METTL3), as a pivotal epigenetic driver of GC pathogenesis. While METTL3 is implicated in promoting tumorigenesis, metastasis, and chemoresistance, a systematic synthesis of its multi-layered regulatory networks and clinical relevance remains elusive. This review comprehensively deciphers METTL3’s dual roles as an oncogene and RNA modifier, elucidating its mechanisms in reprogramming GC progression through m⁶A-dependent RNA stability, translation, and non-coding RNA interactions. We reveal novel axes such as HOXA10-TGFβ /Smad-METTL3, METTL3/IGF2BP3-HDGF-glycolysis, and METTL3-YTHDF1- PARP1-driven chemoresistance, underscoring its cross-talk with oncogenic signaling and metabolic reprogramming. Crucially, we pioneer a clinical perspective by evaluating METTL3’s diagnostic potential as a biomarker and its therapeutic vulnerability in immunotherapy and <i>NSAID</i>-based strategies. Our analysis identifies METTL3 as a central node in GC’s molecular landscape, bridging epigenetic dysregulation with malignant phenotypes and therapy failure. These insights not only redefine METTL3’s role in GC but also provide a roadmap for targeting m⁶A machinery in precision oncology.</p> Graphical Abstract <p><b>Relationship between METTL3 and GC</b></p> <p>By analyzing all available publications reporting the role of METTL3 in GC, this review aims to interpret their relationships. The analysis findings in this review suggest that METTL3 is a risk gene in the GC lifecycle (tumorigenesis, EMT progression, metastasis, and drug resistance), as well as targeting METTL3 is effective for GC treatment. The underlying mechanisms for METTL3 functions include regulating apoptosis, aerobic glycolysis, angiogenesis, and the immune microenvironment of GC cells. In conclusion, this review highlights the clinical potential of METTL3 as a biomarker for diagnosis and a target for treatment in GC.</p> <p>Methyltransferase-3 (METTL3). N<sup>6</sup>-methyladenosine (m<sup>6</sup>A). Gastric cancer (GC). Epithelial-mesenchymal transition (EMT).</p> <p></p>

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METTL3-driven m⁶A epigenetics in gastric cancer: unveiling oncogenic networks and clinical translation from tumorigenesis to therapy resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月26日

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  • Xiaohong Fu,
  • Xia Ruan,
  • Jie He

摘要

Globally, gastric cancer (GC) ranks among the deadliest malignancies due to frequent late-stage detection, metastatic dissemination, and resistance to therapies. Emerging evidence highlights N⁶-methyladenosine (m⁶A) modification, orchestrated by methyltransferase-like 3 (METTL3), as a pivotal epigenetic driver of GC pathogenesis. While METTL3 is implicated in promoting tumorigenesis, metastasis, and chemoresistance, a systematic synthesis of its multi-layered regulatory networks and clinical relevance remains elusive. This review comprehensively deciphers METTL3’s dual roles as an oncogene and RNA modifier, elucidating its mechanisms in reprogramming GC progression through m⁶A-dependent RNA stability, translation, and non-coding RNA interactions. We reveal novel axes such as HOXA10-TGFβ /Smad-METTL3, METTL3/IGF2BP3-HDGF-glycolysis, and METTL3-YTHDF1- PARP1-driven chemoresistance, underscoring its cross-talk with oncogenic signaling and metabolic reprogramming. Crucially, we pioneer a clinical perspective by evaluating METTL3’s diagnostic potential as a biomarker and its therapeutic vulnerability in immunotherapy and NSAID-based strategies. Our analysis identifies METTL3 as a central node in GC’s molecular landscape, bridging epigenetic dysregulation with malignant phenotypes and therapy failure. These insights not only redefine METTL3’s role in GC but also provide a roadmap for targeting m⁶A machinery in precision oncology.

Graphical Abstract

Relationship between METTL3 and GC

By analyzing all available publications reporting the role of METTL3 in GC, this review aims to interpret their relationships. The analysis findings in this review suggest that METTL3 is a risk gene in the GC lifecycle (tumorigenesis, EMT progression, metastasis, and drug resistance), as well as targeting METTL3 is effective for GC treatment. The underlying mechanisms for METTL3 functions include regulating apoptosis, aerobic glycolysis, angiogenesis, and the immune microenvironment of GC cells. In conclusion, this review highlights the clinical potential of METTL3 as a biomarker for diagnosis and a target for treatment in GC.

Methyltransferase-3 (METTL3). N6-methyladenosine (m6A). Gastric cancer (GC). Epithelial-mesenchymal transition (EMT).