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

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 KRAS<sup>G12C</sup> 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 N<sup>6</sup>-methyladenosine methyltransferase, and subsequently regulates m<sup>6</sup>A 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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Publication Details

Journal
Cell Death and Disease
Published
2025-08-30
DOI
https://doi.org/10.1038/s41419-025-07980-8
Citations
3
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
2.42

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article

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

Jianjun Jiang, Zhijie Chen, Shane J. F. Cronin, Meijuan Dian et al.
3 citations
Cell Death and Disease
RNA modifications and cancer
2.42
article

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

Jianjun Jiang, Zhijie Chen, Shane J. F. Cronin, Meijuan Dian, Minghao Yin, Songwen Lin, Shuan Rao, Zehao Zhou, Josef Penninger, Wenqian Liu, Gaoyuan Li, Qingyu Meng, Yan Zhao, Wei-Chao Hao, Yun Liang, Haofei Wang, Tianyuan Liu, Ruihao Zhang, Yujing He, Ming Ji, Zhuoying Yang, Kaican Cai, Tianbao Yan
article en
3 citations

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 KRAS<sup>G12C</sup> 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 N<sup>6</sup>-methyladenosine methyltransferase, and subsequently regulates m<sup>6</sup>A 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.

Cell Death and DiseaseVol. 16(1)
Institute of Molecular Biotechnology (AT), Austrian Academy of Sciences (AT), University of British Columbia (CA), University of Tsukuba (JP), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking Union Medical College Hospital (CN), Nanfang Hospital (CN), First Affiliated Hospital of Guangdong Pharmaceutical University (CN), Helmholtz Centre for Infection Research (DE), Southern Medical University (CN), Medical University of Vienna (AT)
Cancer Research Institute, National Natural Science Foundation of China, Österreichischen Akademie der Wissenschaften, Sun Yat-sen University, OeAD-GmbH, Peking Union Medical College Hospital, Southern Medical University, Nanfang Hospital, Peking Union Medical College, Bundesministerium für Bildung, Wissenschaft und Forschung, Canadian Institutes of Health Research, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences and Peking Union Medical College, Sun Yat-sen University Cancer Center, CIHR Skin Research Training Centre
Openalex Percentile: Top 10%
RNA modifications and cancer
2.42
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