Sodium butyrate induces ferroptosis in colorectal cancer cells by promoting NCOA4-FTH1-mediated ferritinophagy

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 Fe²⁺ levels. 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 Fe²⁺ levels, elevated lipid ROS formation, and altered mitochondrial morphology, without affecting normal FHC cells. Specifically, NaB downregulated FTH1 protein levels, increased lysosomal Fe²⁺, 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 Fe²⁺ and 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.

Colorectal cancer; FTH1; Ferritinophagy; Ferroptosis; NCOA4; Sodium butyrate.