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<p>N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays a crucial role in regulating RNA metabolism and gene expression. Among m6A regulators, METTL3 functions as the catalytic core of the m6A methyltransferase complex and has emerged as a critical epitranscriptomic modulator in cancer. An expanding body of evidence demonstrates that METTL3 is aberrantly expressed in various malignancies, contributing to tumor progression, metastasis, stemness, immune evasion, and resistance to chemotherapy and targeted therapies. Nonetheless, its role remains highly context-dependent, exerting either oncogenic or tumor-suppressive effects based on cancer type and the microenvironment. This review offers an in-depth analysis of the molecular structure and biological functions of METTL3, summarizes its expression profiles and prognostic significance in major human cancers, and examines the mechanisms through which METTL3 modulates tumor biology. In addition, current advancements in the therapeutic targeting of METTL3 are discussed, including small-molecule inhibitors, such as STM2457, their preclinical efficacy, and the challenges and future prospects for clinical translation.</p>

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The role and mechanism of METTL3 in cancer: emerging insights into m6A methylation and therapeutic potential

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Fang Yuan,
  • Wenjuan Zhang,
  • Yuxuan Xia,
  • Xiangqin Zhou,
  • Huihui Gao

摘要

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays a crucial role in regulating RNA metabolism and gene expression. Among m6A regulators, METTL3 functions as the catalytic core of the m6A methyltransferase complex and has emerged as a critical epitranscriptomic modulator in cancer. An expanding body of evidence demonstrates that METTL3 is aberrantly expressed in various malignancies, contributing to tumor progression, metastasis, stemness, immune evasion, and resistance to chemotherapy and targeted therapies. Nonetheless, its role remains highly context-dependent, exerting either oncogenic or tumor-suppressive effects based on cancer type and the microenvironment. This review offers an in-depth analysis of the molecular structure and biological functions of METTL3, summarizes its expression profiles and prognostic significance in major human cancers, and examines the mechanisms through which METTL3 modulates tumor biology. In addition, current advancements in the therapeutic targeting of METTL3 are discussed, including small-molecule inhibitors, such as STM2457, their preclinical efficacy, and the challenges and future prospects for clinical translation.