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

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.