FOXP4 promotes metastatic progression in colorectal cancer through transcriptional activation of BAG3

Metastatic dissemination remains a major cause of mortality in colorectal cancer (CRC), yet the transcriptional basis of epithelial plasticity is not fully understood. Here, we identified Forkhead Box P4 (FOXP4) as a transcription factor associated with CRC progression. Integrated analyses across multiple patient cohorts, together with single-cell transcriptomic data, showed that FOXP4 is preferentially upregulated in malignant epithelial cells and is associated with poor patient survival. FOXP4 depletion impaired malignant phenotypes in vitro and reduced tumor growth, angiogenesis, and liver metastatic burden in vivo. Mechanistically, FOXP4 bound to the promoter region of the co-chaperone BAG3 and regulated its transcription. Consistent with this, BAG3 restoration or silencing partially reversed the phenotypic changes induced by FOXP4 perturbation. These findings suggest that FOXP4 promotes EMT-associated cellular plasticity, at least in part, through BAG3. Together, these results support a FOXP4-BAG3 regulatory axis linked to EMT-related transcriptional programs in CRC. This study provides additional insight into the molecular basis of epithelial plasticity in CRC and supports further investigation of this pathway.