College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
Ecotoxicol Environ Saf. 2024 Oct 1;284:116854. doi: 10.1016/j.ecoenv.2024.116854. Epub 2024 Aug 13.
One of the ways Aflatoxin B1 damages the liver is through ferroptosis. Ferroptosis is characterized by the build-up of lipid peroxides and reactive oxygen species (ROS) due to an excess of iron. Dietary supplements have emerged as a promising strategy for treating ferroptosis in the liver. The flavonoid component hesperetin, which is mostly present in citrus fruits, has a number of pharmacological actions, such as those against liver fibrosis, cancer, and hyperglycemia. However, hesperetin's effects and mechanisms against hepatic ferroptosis are still unknown. In this study, 24 male C57BL/6 J mice were randomly assigned to CON, AFB1 (0.45 mg/kg/day), and AFB1+ hesperetin treatment groups (40 mg/kg/day). The results showed that hesperetin improved the structural damage of the mouse liver, down-regulated inflammatory factors (Cxcl1, Cxcl2, CD80, and F4/80), and alleviated liver fibrosis induced by aflatoxin B1. Hesperetin reduced hepatic lipid peroxidation induced by iron accumulation by up-regulating the levels of antioxidant enzymes (GPX4, GSH-Px, CAT, and T-AOC). It is worth noting that hesperetin not only improved lipid peroxidation but also maintained the dynamic balance of iron ions by reducing ferritin autophagy. Mechanistically, hesperetin's ability to regulate ferritin autophagy mostly depends on the PI3K/AKT/mTOR/ULK1 pathway. In AFB1-induced HepG2 cells, the addition of PI3K inhibitor (LY294002) and AKT inhibitor (Miransertib) confirmed that hesperetin regulated the PI3K/AKT/mTOR/ULK1 pathway to inhibit ferritin autophagy and reduced the degradation of ferritin in lysosomes. In summary, our results suggest that hesperetin not only regulates the antioxidant system but also inhibits AFB1-induced ferritin hyperautophagy, thereby reducing the accumulation of iron ions to mitigate lipid peroxidation. This work provides a fresh perspective on the mechanism behind hesperetin and AFB1-induced liver damage in mice.
黄曲霉毒素 B1 通过铁死亡损伤肝脏的方式之一是通过铁死亡。铁死亡的特征是由于铁过量而导致脂质过氧化物和活性氧 (ROS) 的积累。膳食补充剂已成为治疗肝脏铁死亡的一种有前途的策略。类黄酮成分柚皮素主要存在于柑橘类水果中，具有多种药理作用，如抗肝纤维化、抗癌和降血糖作用。然而，柚皮素对肝铁死亡的作用及其机制尚不清楚。在这项研究中，将 24 只雄性 C57BL/6 J 小鼠随机分为 CON、AFB1（0.45mg/kg/天）和 AFB1+柚皮素治疗组（40mg/kg/天）。结果表明，柚皮素改善了小鼠肝脏的结构损伤，下调了炎症因子（Cxcl1、Cxcl2、CD80 和 F4/80），并缓解了黄曲霉毒素 B1 诱导的肝纤维化。柚皮素通过上调抗氧化酶（GPX4、GSH-Px、CAT 和 T-AOC）水平，减少铁积累引起的肝脂质过氧化。值得注意的是，柚皮素不仅改善了脂质过氧化，还通过减少铁蛋白自噬来维持铁离子的动态平衡。在机制上，柚皮素调节铁蛋白自噬的能力主要依赖于 PI3K/AKT/mTOR/ULK1 通路。在 AFB1 诱导的 HepG2 细胞中，添加 PI3K 抑制剂（LY294002）和 AKT 抑制剂（Miransertib）证实，柚皮素通过调节 PI3K/AKT/mTOR/ULK1 通路抑制铁蛋白自噬，减少溶酶体中铁蛋白的降解。综上所述，我们的结果表明，柚皮素不仅调节抗氧化系统，还抑制 AFB1 诱导的铁蛋白过度自噬，从而减少铁离子的积累，减轻脂质过氧化。这项工作为柚皮素和 AFB1 诱导的小鼠肝脏损伤的机制提供了新的视角。
