2. Academic Validation
  3. The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer

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

  • Nat Cell Biol. 2026 Apr;28(4):797-811. doi: 10.1038/s41556-026-01905-z.
Tianyu Tao # 1 2 3,  Xianming Feng # 1 4,  Yi Yang # 5,  Bangdong Liu # 6,  Jiaer Liang 2,  Zishuo Chen 3,  Shuqi Wang 2,  Jiaqi Zhao 3,  Xiuxiu Yang 2,  Liyun Huo 7,  Youhong Zhang 8,  Zhen Gan 2,  Weibin Wu 9 10,  Jiayu Zeng 9,  Yi Huang 9,  Yaokai Ye 11,  Xuemei Xu 3,  Jianchen Yu 2 12,  Ruohui Hong 2,  Hongyu Guan 13,  Jueheng Wu 2,  Laixin Xia 14,  Weiling He 15,  Bo Li 1 16,  Junchao Cai 17 18 19,  Mengfeng Li 20 21 22
Affiliations

Affiliations

  • 1 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China.
  • 2 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 3 Cancer Institute, Southern Medical University, Guangzhou, China.
  • 4 Integrated Hospital of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
  • 5 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 6 Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.
  • 7 Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 8 General Hospital of Southern Theatre Command, Guangzhou, China.
  • 9 Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 10 Thoracic Surgery Department, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 11 Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 12 Medical School of Shaoguan University, Shaoguan University, Shaoguan, China.
  • 13 Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 14 Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 15 Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 16 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 17 Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 18 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 19 Center of Respiratory Medicine, The First Affiliated Hospital of Guilin Medical University, Guilin, China. [email protected].
  • 20 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, China. [email protected].
  • 21 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 22 Cancer Institute, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41792266 DOI: 10.1038/s41556-026-01905-z
Abstract

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.

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