Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
Toxicology. 2024 Nov;508:153923. doi: 10.1016/j.tox.2024.153923. Epub 2024 Aug 13.
Deoxynivalenol (DON), one of the most common mycotoxins in food and feed, can cause acute and chronic liver injury, posing a serious health risk to humans and animals. One of the important manifestations of DON-induced hepatotoxicity is ferroptosis. It has been reported that CYP2E1 can mediated ferroptosis, but the role of DON-induced CYP2E1 in DON-induced ferroptosis in hepatocytes is unknown. In the present study, we observed that DON significantly increased the expression of CYP2E1 and decreased the expression of the ferroptosis inhibitory proteins GPX4 and SLC7A11, as well as GCLC and NQO1. This resulted in an increase in the levels of cell lipid ROS and FeII, 4-HNE, which ultimately led to cell ferroptosis. Notably, knockdown of CYP2E1 resulted in an increase in DON-induced low levels of GPX4 and SLC7A11, a decrease in DON-induced high levels of lipid ROS, FeII and cell secreted 4-HNE, thus ameliorating cell ferroptosis. Moreover, the ferroptosis inhibitor ferrostatin-1 was observed to antagonise the cell growth inhibitory toxicity induced by DON exposure. This was achieved by blocking the increase in lipid ROS and FeII overload, which in turn reduced the extent of ferroptosis and increased IGF-1 protein expression. In conclusion, the present study demonstrated that CYP2E1 played a regulatory role in DON-induced ferroptosis in hepatocytes. Targeting ferroptosis may prove an effective strategy for alleviating DON-induced cell growth retardation toxicity. These findings provided a potential target and strategies to mitigate DON hepatotoxicity in the future.
脱氧雪腐镰刀菌烯醇（DON）是食品和饲料中最常见的霉菌毒素之一，可导致急性和慢性肝损伤，对人类和动物的健康构成严重威胁。DON 诱导的肝毒性的一个重要表现是铁死亡。据报道，CYP2E1 可以介导铁死亡，但 DON 诱导的 CYP2E1 在肝细胞中 DON 诱导的铁死亡中的作用尚不清楚。在本研究中，我们观察到 DON 显著增加了 CYP2E1 的表达，降低了铁死亡抑制蛋白 GPX4 和 SLC7A11 以及 GCLC 和 NQO1 的表达。这导致细胞脂质 ROS 和 FeII、4-HNE 的水平增加，最终导致细胞铁死亡。值得注意的是，CYP2E1 的敲低导致 DON 诱导的 GPX4 和 SLC7A11 水平升高，DON 诱导的脂质 ROS、FeII 和细胞分泌的 4-HNE 水平降低，从而减轻细胞铁死亡。此外，铁死亡抑制剂 ferrostatin-1 被观察到可拮抗 DON 暴露引起的细胞生长抑制毒性。这是通过阻断脂质 ROS 和 FeII 过载的增加来实现的，从而减少铁死亡的程度并增加 IGF-1 蛋白表达。总之，本研究表明 CYP2E1 在肝细胞中 DON 诱导的铁死亡中发挥调节作用。靶向铁死亡可能是缓解 DON 诱导的细胞生长迟缓毒性的有效策略。这些发现为未来减轻 DON 肝毒性提供了潜在的靶点和策略。
