LINC00839 transcriptionally activated by ELK1 represses ferroptosis in nasopharyngeal carcinoma by regulating UPF1/RCHY1/DJ-1 axis

  • NPJ Precis Oncol. 2026 May 14. doi: 10.1038/s41698-026-01467-1.
Feng Liu  #  1 ,  Yu Li  #  1 ,  Huai Liu  1 ,  Ling Tang  1 ,  ShuWen Fang  2 ,  Xi Wang  2 ,  Pan Chen  1 ,  Hui Wang  1 ,  MeiHua Bao  2  3  4 ,  BinSheng He  2  3  4 ,  Zhen Guo  5  6  7
Affiliations
  • 1. Hunan Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
  • 2. Hunan Provincial Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, the First Clinical College and the First Affiliated Hospital of Changsha Medical University, Changsha Medical University, Changsha, China.
  • 3. Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China.
  • 4. Hunan Provincial Key Laboratory of the Fundamental and Clinical Research on Multimodal Oncology, the First Clinical College and the First Affiliated Hospital of Changsha Medical University, Changsha Medical University, Changsha, China.
  • 5. Hunan Provincial Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, the First Clinical College and the First Affiliated Hospital of Changsha Medical University, Changsha Medical University, Changsha, China. [email protected].
  • 6. Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China. [email protected].
  • 7. Hunan Provincial Key Laboratory of the Fundamental and Clinical Research on Multimodal Oncology, the First Clinical College and the First Affiliated Hospital of Changsha Medical University, Changsha Medical University, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 42135459 DOI: 10.1038/s41698-026-01467-1
Abstract

Ferroptosis induction is a novel strategy for treating human cancers; however, the detailed mechanisms underlying Ferroptosis resistance during nasopharyngeal carcinoma (NPC) progression remain unclear. Herein, we explored the role and potential mechanism of LINC00839 in Ferroptosis resistance of NPC cells. We found that the expression levels of LINC00839 and transcription factor ets-like kinase 1 (ELK1) were elevated in NPC tissues, which were associated with a poor survival of NPC patients. Overexpression of LINC00839 or ELK1 reduced the sensitivity of NPC cells to ferroptosis-inducing drugs. Mechanistically, ELK1 directly bound to LINC00839 promoter to contribute to its transcription. Subsequently, LINC00839 destabilized ring finger and CHY zinc finger domain-containing 1 (RCHY1) mRNA through recruitment of up-frameshift 1 (UPF1), and consequently inhibited ubiquitination and degradation of DJ-1 protein. LINC00839 knockdown induced NPC cell Ferroptosis, which was neutralized by RCHY1 depletion or DJ-1 overexpression. Knockdown of ELK1 or LINC00839 exerted synergistic roles with Erastin or ferroptosis-inducing chemotherapeutic drug Sorafenib to enhance Ferroptosis, thereby delaying tumor growth in vivo. In summary, this study reveals that ELK1-mediated transcription activation of LINC00839 promotes Ferroptosis resistance of NPC cells by destabilizing RCHY1 mRNA and subsequent repressing DJ-1 ubiquitination and degradation. These findings provide potential therapeutic targets for overcoming Ferroptosis resistance in NPC.

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