黄曲霉毒素 B1 损害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景的策略。黄酮类成分橙皮素主要存在于柑橘类水果中，具有多种药理作用，例如抗肝纤维化、癌症和高血糖。然而，橙皮素抗肝铁死亡的作用和机制仍不清楚。在这项研究中，24 只雄性 C57BL/6J 小鼠被随机分配到 CON、AFB1（0.45 毫克/公斤/天）和 AFB1 橙皮素治疗组（40 毫克/公斤/天）。结果表明，橙皮素改善小鼠肝脏的结构损伤，下调炎症因子（Cxcl1、Cxcl2、CD80和F4/80），减轻黄曲霉毒素B1诱导的肝纤维化。橙皮素通过上调抗氧化酶（GPX4、GSH-Px、CAT 和 T-AOC）的水平来减少铁积累引起的肝脏脂质过氧化。值得注意的是，橙皮素不仅可以改善脂质过氧化，还可以通过减少铁蛋白自噬来维持铁离子的动态平衡。从机制上讲，橙皮素调节铁蛋白自噬的能力主要取决于 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）证实橙皮素调节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。总之，我们的结果表明橙皮素不仅可以调节抗氧化系统，还可以抑制 AFB1 诱导的铁蛋白过度自噬，从而减少铁离子的积累，从而减轻脂质过氧化。这项工作为橙皮素和 AFB1 诱导小鼠肝损伤的机制提供了全新的视角。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.