2. Academic Validation
  3. Zearalenone induces intestinal damage and flora disturbance in rats by triggering ferroptosis via the system Xc--GSH-GPX4 signaling pathway

Zearalenone induces intestinal damage and flora disturbance in rats by triggering ferroptosis via the system Xc--GSH-GPX4 signaling pathway

  • Ecotoxicol Environ Saf. 2025 Sep 1:302:118600. doi: 10.1016/j.ecoenv.2025.118600.
Bingxin Huangfu 1,  Jie Li 2,  Tongxiao Xu 1,  Xinxin Ren 1,  Ruiqi Zhang 1,  Yanan Chen 3,  Jiantang Wang 1,  Kunlun Huang 4,  Xiaoyun He 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 College of Veterinary Medicine, China Agricultural University, Beijing 100094, PR China.
  • 4 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 Safety Assessment of Genetically Modified Organism (Food Safety), The Ministry of Agriculture and Rural Affairs of the PR China, Beijing 100083, PR China.
  • 5 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 Safety Assessment of Genetically Modified Organism (Food Safety), The Ministry of Agriculture and Rural Affairs of the PR China, Beijing 100083, PR China. Electronic address: hexiaoyun@cau.edu.cn.
PMID: 40592152 DOI: 10.1016/j.ecoenv.2025.118600
Abstract

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.

Keywords

Colon damage; Ferroptosis; Inflammation; Intestinal flora; Zearalenone.

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