The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer PMID: 41792266

ADC Targets in Oncology

2026-04-10

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

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.

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.