Huangfu Bingxin, Li Jie, Xu Tongxiao, Ren Xinxin, Zhang Ruiqi, Chen Yanan, Wang Jiantang, Huang Kunlun, He Xiaoyun
Key Laboratory of Precision Nutrition and Food Quality, Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, PR China.
Key Laboratory of Precision Nutrition and Food Quality, Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, PR China; Beijing Grain Science Research Institute, Beijing 100162, PR China.
Ecotoxicol Environ Saf. 2025 Sep 1;302:118600. doi: 10.1016/j.ecoenv.2025.118600. Epub 2025 Jun 30.
Zearalenone (ZEA) is a mycotoxin commonly found in contaminated grains. The colon, a primary site of ZEA exposure, serves as a barrier to prevent its systemic entry. Ferroptosis signaling in intestinal epithelial cells is associated with increased intestinal inflammation. However, the role of ferroptosis in ZEA-induced gut injury is unclear. This study examined the effects of ZEA on ferroptosis signaling in Sprague-Dawley (SD) rats (5 mg/kg body weight, gavage for three weeks) and Caco-2 intestinal epithelial cells (20 μM, 24-hour treatment). ZEA exposure significantly increased intestinal permeability in rats and reduced transepithelial electrical resistance (TEER) in Caco-2 cells. The mRNA expression analysis and protein analyses revealed a marked reduction in tight junction protein expression and increased pro-inflammatory cytokines. ZEA treatment also led to significant iron accumulation in both rat colonic tissue and Caco-2 cells, accompanied by mitochondrial shrinkage and cristae reduction, indicating ferroptosis induction. Further analysis showed that ZEA suppressed system Xc (SLC7A11 and SLC3A2) expression, reducing glutathione (GSH) levels and down-regulating GPX4, thereby impairing lipid peroxidation clearance. Additionally, ZEA exposure altered gut microbiota composition by decreasing beneficial bacteria and increasing harmful ones, with these microbial changes correlating with ferroptosis markers. In conclusion, ZEA induces colonic ferroptosis by disrupting the system Xc-GSH-GPX4 axis, and gut microbiota alterations may contribute to this process.
玉米赤霉烯酮（ZEA）是一种常见于受污染谷物中的霉菌毒素。结肠是ZEA暴露的主要部位，作为一道屏障可防止其进入全身。肠道上皮细胞中的铁死亡信号与肠道炎症增加有关。然而，铁死亡在ZEA诱导的肠道损伤中的作用尚不清楚。本研究检测了ZEA对Sprague-Dawley（SD）大鼠（5mg/kg体重，灌胃三周）和Caco-2肠道上皮细胞（20μM，处理24小时）铁死亡信号的影响。ZEA暴露显著增加了大鼠的肠道通透性，并降低了Caco-2细胞的跨上皮电阻（TEER）。mRNA表达分析和蛋白质分析显示紧密连接蛋白表达显著降低，促炎细胞因子增加。ZEA处理还导致大鼠结肠组织和Caco-2细胞中铁显著蓄积，伴有线粒体萎缩和嵴减少，表明诱导了铁死亡。进一步分析表明，ZEA抑制系统Xc（SLC7A11和SLC3A2）的表达，降低谷胱甘肽（GSH）水平并下调GPX4，从而损害脂质过氧化清除。此外，ZEA暴露通过减少有益菌并增加有害菌改变了肠道微生物群组成，这些微生物变化与铁死亡标志物相关。总之，ZEA通过破坏系统Xc-GSH-GPX4轴诱导结肠铁死亡，肠道微生物群改变可能促成这一过程。
