A novel piperine derivative HJJ_3_5 inhibits colorectal cancer progression by modulating EMT signaling pathways.

Colorectal cancer (CRC) is a fatal cancer prevalent worldwide, and epithelial-mesenchymal transition (EMT) is a key factor in tumor invasion and metastasis. Piperine, a natural alkaloid known for its antitumor properties, faces limitations in clinical use due to its moderate potency. To address this, our team synthesized and validated a new derivative, HJJ_3_5, which has shown potent antitumor activity against CRC cells. We assessed HJJ_3_5's inhibitory effects on the colon cancer cell line HCT116 through MTT, colony formation, and assays for cell migration and invasion. To uncover HJJ_3_5's molecular mechanisms, we utilized transcriptomics, weighted gene co-expression network analysis (WGCNA), and machine learning to identify key EMT-related genes. Western blot and immunofluorescence experiments confirmed the expression changes of these key proteins. Our findings indicate that HJJ_3_5 significantly suppressed the proliferation, migration, and invasion of HCT116 cells in vitro, outperforming piperine. We discovered that HJJ_3_5 downregulated the expression of COL12A1, PJA2, VCAN, MEF2C, DPYD, and DDR2 genes in HCT116 cells, which resulted in a decrease in the EMT regulator SNAI1, thus inhibiting EMT in these cells. In summary, this study presents novel evidence that the piperine derivative HJJ_3_5 inhibits the migration and invasion of colorectal cancer cells through SNAI1-mediated EMT.