Liu Lulin, Liu Yingyin, Zhou Xin, He Huaxing, Chen Nachuan, Qin Yong, Sun Xiaodie, Bian Zhongbo, Zhang Qiuyu, Mao Lianzhi, Sun Suxia
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.
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.
Int Immunopharmacol. 2025 Jul 12;163:115188. doi: 10.1016/j.intimp.2025.115188.
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 Fe 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 Fe levels, 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 Fe 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.
结直肠癌（CRC）是一种常见的恶性肿瘤，治疗选择有限，这凸显了对新型有效治疗方法的需求。铁死亡是一种与铁蛋白自噬和铁代谢相关的程序性细胞死亡形式，是一种诱导癌细胞死亡的有前景的选择性方法。丁酸钠（NaB）是一种源自膳食纤维的代谢产物，已被证明可在CRC HCT-116细胞中诱导铁死亡，但其潜在机制仍不清楚。本研究调查NaB是否通过NCOA4-FTH1途径经由铁蛋白自噬在CRC细胞中诱导铁死亡，从而影响细胞内铁水平。我们的结果表明，NaB处理（4 mM，36小时）可在CRC HCT-116和Caco-2细胞中诱导铁死亡，表现为细胞增殖受抑制、铁水平升高、脂质活性氧生成增加以及线粒体形态改变，而不影响正常FHC细胞。具体而言，NaB下调CRC细胞中FTH1蛋白水平，增加溶酶体铁，并增强NCOA4-FTH1共定位。机制上，NaB通过NCOA4-FTH1途径促进铁蛋白自噬。在人结直肠癌异种移植模型中，NaB抑制肿瘤生长，增加细胞内铁和NCOA4水平，并降低FTH1水平。这些发现表明，NaB通过NCOA4-FTH1途径诱导铁蛋白自噬，从而促进CRC细胞中的铁死亡，凸显了其作为抗CRC抗癌剂的潜力。
