2. Academic Validation
  3. Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis

Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis

  • Cell Death Dis. 2025 Aug 30;16(1):660. doi: 10.1038/s41419-025-07980-8.
Meijuan Dian # 1,  Liang Yun # 1,  Qingyu Meng # 2,  Songwen Lin # 3,  Ming Ji # 3,  Ying Zhou 4,  Wenqian Liu 3,  Zhuoying Yang 1,  Yayan Zhao 5,  Gaoyuan Li 6,  Jianjun Jiang 1,  Weichao Hao 5,  Zhijie Chen 1,  Zehao Zhou 1,  Ruihao Zhang 1,  Tianyuan Liu 7,  Yujing He 1,  Tianbao Yan 1,  Haofei Wang 1,  Shane J F Cronin 8 9,  Josef M Penninger 10 11 12 13,  Kaican Cai 14,  Shuan Rao 15
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 4 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 5 Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
  • 6 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • 7 Tsukuba Life Science Innovation Program, University of Tsukuba, Tsukuba, Japan.
  • 8 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 9 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
  • 10 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. josef.penninger@ubc.ca.
  • 11 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. josef.penninger@ubc.ca.
  • 12 Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. josef.penninger@ubc.ca.
  • 13 Helmholtz Centre for Infection Research, Braunschweig, Germany. josef.penninger@ubc.ca.
  • 14 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. caican@smu.edu.cn.
  • 15 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. raoshuan1@smu.edu.cn.
  • # Contributed equally.
PMID: 40885716 DOI: 10.1038/s41419-025-07980-8
Abstract

Approximately 30% of human cancers carry various Ras mutations, including KRAS, NRAS, and HRAS. Among these mutations, KRAS is the most prevalent isoform detected in lung Cancer. While several small molecular inhibitors targeting specifically KRASG12C have been developed and tested clinically, alternative approaches are still necessary due to expected drug resistance. In this study, we present evidence that the loss of DDX3X significantly delays tumor progression in various KRAS-driven lung Cancer models. Inhibition of DDX3X disrupts cysteine and glutathione metabolism, thereby inducing Ferroptosis in lung Cancer cells. This effect is primarily mediated by the downregulation of Cystathionine-β-synthase (CBS), the rate-limiting enzyme in cysteine generation. Mechanistically, DDX3X directly binds to the transcription factor JUND, which mediates the transcriptional regulation of METTL16, a key N6-methyladenosine methyltransferase, and subsequently regulates m6A modification and translation of CBS transcripts. This cascade induces hypermethylation and high expression of CBS, consequently triggering cysteine production and maintaining antioxidative homeostasis, which is essential for the survival of KRAS-driven lung Cancer cells. Finally, we demonstrate that a newly developed DDX3X PROTAC degrader J10 efficiently delays lung Cancer progression with multiple advantages compared to DDX3X small molecular inhibitor RK-33 and limited side effects. These findings unveil the potential of DDX3X as a valuable target for Adjuvant therapies in managing KRAS-driven lung Cancer.

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