Hyperoside regulates iron death-mediated zearalenone poisoning through Nrf2/GPX4 pathway, causing blood- testosterone barrier injury in pigs

Abstract Zearalenone (ZEA) is an estrogenic mycotoxin produced by Fusarium, which widely contaminates cereals and threatens animal and human health through the food chain. This study aims to investigate the testicular toxicity of ZEA and the intervention effect of Hyperoside (HYP) in a 30-day-old Luchuan miniature pig model. The results showed that ZEA (3.2 mg/kg diet) exposure significantly decreased serum testosterone level, increased estradiol content, and induced oxidative stress (increased MDA and H 2 O 2 , decreased GSH) and ferroptosis (iron ion accumulation and decreased GPX4/Nrf2 expression) in the testis. It damages the blood-testis barrier (BTB) by destroying tight junction proteins (Occludin, Claudin-11, etc.), leading to reduced numbers of spermatogenic cells and abnormal mitochondrial structure. HYP (2.5 mg/kg body weight) significantly alleviated ZEA-induced oxidative damage, restored GSH level, reduced iron content, and up-regulated Nrf2/GPX4 pathway to inhibit ferroptosis. At the same time, HYP can improve testicular function by repairing the BTB structure and reducing histopathological damage. This study revealed the mechanism by which HYP alleviated ZEA reproductive toxicity by activating antioxidant and ferroptosis pathways, and provided a potential strategy for preventing and treating ZEA pollution.