Differential Effects of Saturated and Unsaturated Fatty Acids on Colorectal Cancer via IDO1 Signaling

BACKGROUND: Colorectal cancer (CRC) incidence has risen significantly in China, potentially linked to dietary Westernization and increased consumption of high-fat diets (HFD). METHODS: This study examines the differential effects of various fatty acids-saturated (palmitic acid, PA), monounsaturated (oleic acid, OA), and polyunsaturated (arachidonic acid, AA; docosahexaenoic acid, DHA)-on CRC progression, focusing on the IDO1/AhR signaling pathway. RESULTS: Clinical data indicate that CRC patients exhibit elevated serum lipid levels, with PA promoting cell proliferation, migration, and invasion more strongly than unsaturated fatty acids. The pro-tumorigenic effects of PA are enhanced in the presence of lipopolysaccharide (LPS), suggesting an interaction between diet and gut microbiota. In vivo experiments corroborate that a high-PA diet significantly elevates tumor growth and IDO1 expression compared to DHA. Mechanistic analyses reveal that PA and LPS co-stimulation activates the IDO1-AhR-PI3K/Akt-NF-κB pathway, which is implicated in CRC progression. CONCLUSIONS: These findings suggest that saturated fatty acids, particularly PA, may exacerbate CRC development risk through metabolic dysregulation, highlighting the potential of IDO1 as a biomarker for CRC associated with HFD. Reducing dietary saturated fat intake may thus be a viable strategy for CRC prevention.