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Peer-reviewedCC BY 4.0Advanced Science

NDFIP2 Suppresses Colorectal Cancer Metastasis Through DDX3X‐Dependent R‐Loop Remodeling and GNG13 Transcriptional Activation

  • Enjian Zhang1,2,3
  • Yanfang Li1,2,3
  • Jiaxin Shu1,2,3
  • Shang Xu1,2
  • Heng Lv1
  • Chong Zhang1
  • Pengbo Zhang1
  • Nai Wu1
  • Shuai Gong1
  • Xiuzhong Zhang1
  • Zeqiang Ren1
  • Yi Zhang1,2,4,3
1 more authors
  • Xin Liu5,6
6 affiliations
  1. 1Department of Gastrointestinal Surgery Affiliated Hospital of Xuzhou Medical University Xuzhou China
  2. 2Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology Xuzhou Medical University Xuzhou China
  3. 3Technology Innovation and Public Service Center Huaihai Medical Science and Technology Innovation Center The Affiliated Hospital of Xuzhou Medical University Xuzhou China
  4. 4Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Houston Texas USA
  5. 5Department of Endocrinology Affiliated Hospital of Xuzhou Medical University Xuzhou China
  6. 6Department of Biology and Biochemistry Center For Nuclear Receptors and Cell Signaling University of Houston Houston Texas USA
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Abstract

Distant metastasis remains the leading cause of colorectal cancer (CRC) mortality, yet the underlying molecular mechanisms remain incompletely defined. Integrating RNA sequencing (RNA‐seq) profiling and clinical validation, we identified NDFIP2 as significantly downregulated in metastatic CRC. Functionally, NDFIP2 loss drove epithelial‐mesenchymal transition (EMT), stemness, and metastasis via PI3K/AKT hyperactivation. Mechanistically, NDFIP2 serves as an adaptor recruiting the E3 ligase NEDD4 to induce K48‐linked polyubiquitination and proteasomal degradation of DDX3X. Unrestrained DDX3X resolves R‐loops at the GNG13 promoter and recruits the transcription factor CTCF, synergistically enhancing GNG13 transcription to amplify PI3K/AKT signaling. Targeting this vulnerability, we engineered a cell‐permeable NDFIP2‐derived iRGD‐conjugated peptide (ND‐iRGD). In vivo administration of this construct suppressed DDX3X/GNG13/PI3K/AKT signaling, thereby attenuating distant metastasis and prolonging murine survival. Collectively, NDFIP2 acts as a critical metastasis suppressor via the DDX3X/R‐loop/GNG13 axis, presenting the ND‐iRGD peptide as a promising translatable therapeutic strategy for metastatic CRC.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026ndfip2,
  title = {{NDFIP2 Suppresses Colorectal Cancer Metastasis Through DDX3X‐Dependent R‐Loop Remodeling and GNG13 Transcriptional Activation}},
  author = {Enjian Zhang and Yanfang Li and Jiaxin Shu and Shang Xu and Heng Lv and Chong Zhang and Pengbo Zhang and Nai Wu and Shuai Gong and Xiuzhong Zhang and Zeqiang Ren and Yi Zhang and Xin Liu},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78466},
  url = {https://doi.org/10.1002/advs.78466},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - NDFIP2 Suppresses Colorectal Cancer Metastasis Through DDX3X‐Dependent R‐Loop Remodeling and GNG13 Transcriptional Activation
AU  - Enjian Zhang
AU  - Yanfang Li
AU  - Jiaxin Shu
AU  - Shang Xu
AU  - Heng Lv
AU  - Chong Zhang
AU  - Pengbo Zhang
AU  - Nai Wu
AU  - Shuai Gong
AU  - Xiuzhong Zhang
AU  - Zeqiang Ren
AU  - Yi Zhang
AU  - Xin Liu
PY  - 2026
DA  - 2026/10/31
JO  - Advanced Science
DO  - 10.1002/advs.78466
UR  - https://doi.org/10.1002/advs.78466
AB  - Distant metastasis remains the leading cause of colorectal cancer (CRC) mortality, yet the underlying molecular mechanisms remain incompletely defined. Integrating RNA sequencing (RNA‐seq) profiling and clinical validation, we identified NDFIP2 as significantly downregulated in metastatic CRC. Functionally, NDFIP2 loss drove epithelial‐mesenchymal transition (EMT), stemness, and metastasis via PI3K/AKT hyperactivation. Mechanistically, NDFIP2 serves as an adaptor recruiting the E3 ligase NEDD4 to induce K48‐linked polyubiquitination and proteasomal degradation of DDX3X. Unrestrained DDX3X resolves R‐loops at the GNG13 promoter and recruits the transcription factor CTCF, synergistically enhancing GNG13 transcription to amplify PI3K/AKT signaling. Targeting this vulnerability, we engineered a cell‐permeable NDFIP2‐derived iRGD‐conjugated peptide (ND‐iRGD). In vivo administration of this construct suppressed DDX3X/GNG13/PI3K/AKT signaling, thereby attenuating distant metastasis and prolonging murine survival. Collectively, NDFIP2 acts as a critical metastasis suppressor via the DDX3X/R‐loop/GNG13 axis, presenting the ND‐iRGD peptide as a promising translatable therapeutic strategy for metastatic CRC.
SN  - 2198-3844
ER  -