and colorectal cancer: A paradoxical role revealed through metabolite profiling and prognostic modeling.

BACKGROUND

Emerging evidence implicates () in human oncogenesis. Notably, studies have supported its involvement in regulating outcomes in colorectal cancer (CRC). This study investigated the paradoxical role of in CRC, aiming to determine whether it promotes or suppresses tumor development, with a focus on the mechanistic basis linked to its metabolic profile.

AIM

To investigate the dual role of in the development and progression of CRC through metabolite profiling and to establish a prognostic model that integrates the microbial and metabolic interactions in CRC, providing insights into potential therapeutic strategies and clinical outcomes.

METHODS

A prognostic model integrating with CRC was developed, incorporating enrichment analysis, immune infiltration profiling, survival analysis, Mendelian randomization, single-cell sequencing, and spatial transcriptomics. The effects of the metabolite mixture on CRC cells were subsequently validated . The primary metabolite composition was characterized using liquid chromatography-mass spectrometry.

RESULTS

A prognostic model based on five specific mRNA markers, , , , , and , was established. The metabolite mixture significantly reduced CRC cell viability. Post-treatment analysis revealed a significant decrease in gene expression in HT29 cells, while the expression levels of , , and were significantly elevated in HCT116 cells. Conversely, expression and that of other CRC cell lines showed reductions. In normal colonic epithelial cells (NCM460), , , and expression levels were significantly increased, while and levels were markedly reduced. Following metabolite treatment, the invasive and migratory capabilities of NCM460, HT29, and HCT116 cells were reduced. Quantitative analysis of extracellular ATP post-treatment showed a significant elevation ( < 0.01). The metabolite mixture had no effect on reactive oxygen species accumulation in CRC cells but led to a reduction in mitochondrial membrane potential, increased intracellular lipid peroxidation, and induced apoptosis. Metabolomic profiling revealed significant alterations, with 516 metabolites upregulated and 531 downregulated.

CONCLUSION

This study introduced a novel prognostic model for CRC risk assessment. The findings suggested that the metabolite mixture exerted an inhibitory effect on CRC initiation.