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

Lulin Liu; Yingyin Liu; Xin Zhou; Huaxing He; Nachuan Chen; Yong Qin; Xiaodie Sun; Zhongbo Bian; Qiuyu Zhang; Lianzhi Mao; Suxia Sun

doi:10.1016/j.intimp.2025.115188

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

Int Immunopharmacol. 2025 Jul 12:163:115188. doi: 10.1016/j.intimp.2025.115188. Online ahead of print.

Authors

Lulin Liu¹, Yingyin Liu¹, Xin Zhou¹, Huaxing He¹, Nachuan Chen¹, Yong Qin¹, Xiaodie Sun¹, Zhongbo Bian¹, Qiuyu Zhang¹, Lianzhi Mao¹, Suxia Sun²

Affiliations

¹ Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China.
² Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China. Electronic address: suxiasun@hotmail.com.

PMID: 40652583
DOI: 10.1016/j.intimp.2025.115188

Abstract

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.

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