Crocetin suppresses colorectal cancer progression by targeting TGM2 and inhibiting the JAK2/STAT3 pathway.

BACKGROUND: Colorectal cancer (CRC) is a major health threat with limited therapies for advanced stages. Crocetin, a natural compound from saffron, has broad anticancer potential, but its mechanisms in CRC are unclear.

METHODS: A CRC xenograft mouse model was established to evaluate the antitumor effect of crocetin. Next, transcriptomic analysis was performed to identify differentially expressed genes (DEGs) in tumor tissues of tumor-bearing mice between the crocetin treatment and control groups. Through the integration of network pharmacology, and protein-protein interaction (PPI) network analysis, potential key target genes regulated by crocetin in CRC were identified. Functional assays (e.g. CCK-8 and transwell assays) were employed to assess the biological role of crocetin and its target gene, TGM2, in CRC cells.

RESULTS: Crocetin significantly inhibited tumor growth in HCT116-tumor-bearing mice in vivo. Transcriptomic analysis identified 2,577 DEGs in tumor tissues between the crocetin and control groups. Through integrated network pharmacology, transcriptomics, and molecular docking analyses, we identified five potential crocetin-targeted genes-ADAM17, DNMT1, MTOR, TGM2, and XRCC6-all of which showed significant downregulation following crocetin treatment. Furthermore, in vitro experiments demonstrated that crocetin notably suppressed cell viability, migration, and invasion, as well as reduced the expression of TGM2, p-JAK2, and p-STAT3 in HCT116 cells; however, the tumor-suppressive effects of crocetin were markedly abolished by TGM2 overexpression.

CONCLUSION: Collectively, crocetin could suppress CRC progression by targeting TGM2/JAK2/STAT3 signaling pathway, supporting its potential as a therapeutic agent for CRC.