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<p>Chemoresistance remains a major barrier to achieving durable therapeutic responses in colorectal cancer (CRC). Emerging evidence implicates N6-methyladenosine (m6A) RNA modification in drug-response regulation, yet its mechanistic contribution to CRC chemoresistance requires further clarification. Here, we identified a pivotal METTL3–YTHDF1–MYC regulatory axis governing 5-fluorouracil (5-FU) resistance through integrative transcriptomic, epitranscriptomic, and functional analyses. RNA-seq and MeRIP-seq demonstrated that METTL3-mediated m6A deposition is significantly elevated in resistant CRC cells, with MYC emerging as the key downstream target. Functional and biochemical assays demonstrated that METTL3-mediated m6A marks regulate MYC mRNA stability and translational output in a YTHDF1-dependent manner, rather than acting as a direct stabilizing signal, thereby sustaining MYC overexpression. Mechanistically, MYC directly activates DNA repair genes, including BRCA1 and RAD51, and upregulates glycolytic regulators LDHA and HK2, thereby augmenting DNA damage repair capacity and glycolytic flux. Silencing METTL3 or YTHDF1 restored chemosensitivity, whereas MYC overexpression partially rescued this phenotype, establishing MYC as a functional effector of m6A-dependent drug resistance. Finally, a multi-gene predictive model derived from the m6A–MYC axis robustly distinguished chemosensitive from chemoresistant CRC samples, providing clinically relevant insights for treatment stratification. Collectively, this study reveals that m6A-regulated MYC signaling orchestrates DNA repair and metabolic remodeling to promote CRC chemoresistance and highlights the METTL3–YTHDF1–MYC axis as a promising target for predictive precision therapy and combined therapeutic interventions.</p>

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METTL3–YTHDF1–driven m6A enhancement of MYC signaling orchestrates DNA repair and metabolic reprogramming to promote chemoresistance in colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Kai Wang,
  • Song Geng,
  • Zhengping Xiao,
  • Hong Jiang,
  • Hong Jiang

摘要

Chemoresistance remains a major barrier to achieving durable therapeutic responses in colorectal cancer (CRC). Emerging evidence implicates N6-methyladenosine (m6A) RNA modification in drug-response regulation, yet its mechanistic contribution to CRC chemoresistance requires further clarification. Here, we identified a pivotal METTL3–YTHDF1–MYC regulatory axis governing 5-fluorouracil (5-FU) resistance through integrative transcriptomic, epitranscriptomic, and functional analyses. RNA-seq and MeRIP-seq demonstrated that METTL3-mediated m6A deposition is significantly elevated in resistant CRC cells, with MYC emerging as the key downstream target. Functional and biochemical assays demonstrated that METTL3-mediated m6A marks regulate MYC mRNA stability and translational output in a YTHDF1-dependent manner, rather than acting as a direct stabilizing signal, thereby sustaining MYC overexpression. Mechanistically, MYC directly activates DNA repair genes, including BRCA1 and RAD51, and upregulates glycolytic regulators LDHA and HK2, thereby augmenting DNA damage repair capacity and glycolytic flux. Silencing METTL3 or YTHDF1 restored chemosensitivity, whereas MYC overexpression partially rescued this phenotype, establishing MYC as a functional effector of m6A-dependent drug resistance. Finally, a multi-gene predictive model derived from the m6A–MYC axis robustly distinguished chemosensitive from chemoresistant CRC samples, providing clinically relevant insights for treatment stratification. Collectively, this study reveals that m6A-regulated MYC signaling orchestrates DNA repair and metabolic remodeling to promote CRC chemoresistance and highlights the METTL3–YTHDF1–MYC axis as a promising target for predictive precision therapy and combined therapeutic interventions.