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

Jul 13, 2025International immunopharmacology

Sodium butyrate may cause iron-related cell death in colorectal cancer by increasing ferritin breakdown

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Abstract

Sodium butyrate (NaB) treatment at 4 mM for 36 hours induced ferroptosis in colorectal cancer HCT-116 and Caco-2 cells.

NaB treatment inhibited cell proliferation and increased intracellular iron levels in colorectal cancer cells.
Elevated lipid reactive oxygen species (ROS) formation and altered mitochondrial morphology were observed following NaB treatment.
NaB downregulated FTH1 protein levels and increased lysosomal iron in colorectal cancer cells.
The NCOA4-FTH1 pathway was involved in the promotion of ferritinophagy by NaB.
In a human colorectal cancer xenograft model, NaB inhibited tumor growth and altered intracellular levels of NCOA4 and FTH1.

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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+

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

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