Colorectal cancer (CRC) is a prevalent malignant tumor with limited therapeutic options, underscoring the need for novel and effective treatments. Ferroptosis, a form of programmed cell death associated with ferritinophagy and iron metabolism, presents a promising selective approach to inducing cancer cell death. Sodium butyrate (NaB), a metabolite derived from dietary fiber, has been shown to induce ferroptosis in CRC HCT-116 cells, though its underlying mechanism remains unclear. This study investigates whether NaB induces ferroptosis in CRC cells via ferritinophagy through the NCOA4-FTH1 pathway, thereby affecting intracellular Felevels. Our results demonstrate that NaB treatment (4 mM for 36 h) induced ferroptosis in CRC HCT-116 and Caco-2 cells, as evidenced by inhibited cell proliferation, increased Felevels, elevated lipid ROS formation, and altered mitochondrial morphology, without affecting normal FHC cells. Specifically, NaB downregulated FTH1 protein levels, increased lysosomal Fe, and enhanced NCOA4-FTH1 colocalization in CRC cells. Mechanistically, NaB promoted ferritinophagy through the NCOA4-FTH1 pathway. In a human colorectal cancer xenograft model, NaB inhibited tumor growth, increased intracellular Feand NCOA4 levels, and decreased FTH1 levels. These findings suggest that NaB promotes ferroptosis in CRC cells by inducing ferritinophagy via the NCOA4-FTH1 pathway, highlighting its potential as an anticancer agent against CRC. 2+ 2+ 2+ 2+
