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<p>How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species–NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the m<sup>6</sup>A-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize <i>ATF4</i> mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER–ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.</p>

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The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer

  • 期刊论文

  • 发表日期：

    2026年3月6日

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  • Tianyu Tao,
  • Xianming Feng,
  • Yi Yang,
  • Bangdong Liu,
  • Jiaer Liang,
  • Zishuo Chen,
  • Shuqi Wang,
  • Jiaqi Zhao,
  • Xiuxiu Yang,
  • Liyun Huo,
  • Youhong Zhang,
  • Zhen Gan,
  • Weibin Wu,
  • Jiayu Zeng,
  • Yi Huang,
  • Yaokai Ye,
  • Xuemei Xu,
  • Jianchen Yu,
  • Ruohui Hong,
  • Hongyu Guan,
  • Jueheng Wu,
  • Laixin Xia,
  • Weiling He,
  • Bo Li,
  • Junchao Cai,
  • Mengfeng Li

摘要

How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species–NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the m6A-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize ATF4 mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER–ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.