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<p>Liver cancer remains one of the leading causes of cancer-related mortality worldwide, with its progression driven by uncontrolled cell proliferation and evasion of apoptosis. N1-methyladenosine (m<sup>1</sup>A) is a prevalent RNA modification implicated in cancer progression, yet its role in liver cancer remains unclear. Here, we report a significant reduction in m<sup>1</sup>A levels in liver cancer tissues, which contributes to apoptosis evasion in liver cancer cells. We demonstrate that ALKBH3, an m<sup>1</sup>A demethylase, regulates apoptosis by modulating BIRC2 expression. Specifically, ALKBH3 depletion destabilizes BIRC2 mRNA by promoting its degradation, facilitated by m<sup>1</sup>A modifications at positions A98/99/100 in the 5'-UTR of BIRC2. These modifications enhance the interaction between BIRC2 mRNA and the YTHDF3/CNOT1–XRN2 complex, thereby driving mRNA degradation. In vitro, in vivo, and clinical analyses validate the critical role of the m<sup>1</sup>A/BIRC2 axis in regulating apoptosis and tumor progression in liver cancer. Our findings underscore the therapeutic potential of targeting the m<sup>1</sup>A/BIRC2 axis to overcome apoptosis resistance in liver cancer, offering new avenues for intervention in this malignancy.</p>

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m1A-mediated regulation of BIRC2 mRNA stability drives apoptosis evasion and tumor progression in liver cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Yingmin Wu,
  • Shenjie Zhang,
  • Shilong Zhang,
  • Jieyu Lu,
  • Yuntao Yang,
  • Zhirui Zeng,
  • Shan Lei,
  • Rui Mi,
  • Yewei Zhang,
  • Lichen Ge,
  • Tengxiang Chen,
  • Haiyang Li

摘要

Liver cancer remains one of the leading causes of cancer-related mortality worldwide, with its progression driven by uncontrolled cell proliferation and evasion of apoptosis. N1-methyladenosine (m1A) is a prevalent RNA modification implicated in cancer progression, yet its role in liver cancer remains unclear. Here, we report a significant reduction in m1A levels in liver cancer tissues, which contributes to apoptosis evasion in liver cancer cells. We demonstrate that ALKBH3, an m1A demethylase, regulates apoptosis by modulating BIRC2 expression. Specifically, ALKBH3 depletion destabilizes BIRC2 mRNA by promoting its degradation, facilitated by m1A modifications at positions A98/99/100 in the 5'-UTR of BIRC2. These modifications enhance the interaction between BIRC2 mRNA and the YTHDF3/CNOT1–XRN2 complex, thereby driving mRNA degradation. In vitro, in vivo, and clinical analyses validate the critical role of the m1A/BIRC2 axis in regulating apoptosis and tumor progression in liver cancer. Our findings underscore the therapeutic potential of targeting the m1A/BIRC2 axis to overcome apoptosis resistance in liver cancer, offering new avenues for intervention in this malignancy.