胶质瘤是起源于胶质细胞的神经系统最常见的原发性恶性肿瘤。其高侵袭性和复发性给其有效治疗带来了重大挑战。铁死亡是一种新型的可编程细胞死亡方式，其特征为细胞内铁超载和脂质过氧化物的积累。现有研究已证明了有针对性的铁死亡治疗在胶质瘤治疗中的有效性。本研究利用叶酸（FA）修饰的层状双氢氧化物负载辛伐他汀（SIM）构建了一种新型铁死亡纳米药物（FA-LDH@SIM）。制备的纳米药物提高了SIM对胶质瘤的治疗效果。与游离SIM相比，FA-LDH@SIM显示出更强的细胞毒性，显著抑制了胶质瘤细胞的增殖，并且显著抑制了胶质瘤的侵袭和迁移能力。此外，SIM能够诱导某些铁死亡指标的变化，包括细胞内脂质过氧化物、ROS和MDA水平的增加，GSH产生的减少，二价铁水平的增加，以及线粒体形态的变化。进一步实验证明，SIM通过下调HMGCR表达和抑制甲萘酮途径下调GPX4表达来诱导肿瘤细胞的铁死亡。此外，FA-LDH@SIM组在动物胶质瘤模型中治疗后明显抑制了肿瘤生长。这些结果表明，FA-LDH@SIM纳米载药系统在体外和体内均表现出优异的抗肿瘤效果，并且是治疗胶质瘤的有效方法。版权所有 © 2023. 由Elsevier Inc.出版。

Glioma is the most common primary malignant tumor of the nervous system that starts in the glial cells. Its high invasiveness and recurrence pose major challenges to its effective treatment. Ferroptosis is a new type of programmed cell death characterized by intracellular iron overload and accumulation of lipid peroxides. Existing studies have demonstrated the efficacy of targeted ferroptosis therapy in the treatment of glioma. In this study, folic acid (FA)-modified layered double hydroxide loaded with simvastatin (SIM), a ferroptosis drug, was used to prepare a novel ferroptosis nanodrug (FA-LDH@SIM). The prepared nanodrug improved the therapeutic effect of SIM on glioma. Compared with free SIM, FA-LDH@SIM showed greater cytotoxicity, significantly inhibited glioma cell proliferation, and significantly inhibited glioma invasion and migration ability. Furthermore, SIM could induce changes in certain ferroptosis indicators, including increased intracellular LPO, ROS and MDA level, decreased GSH production, increased divalent iron level, and changes in mitochondrial morphology. Further experiments revealed that SIM induced ferroptosis in tumor cells by down-regulating HMGCR expression and inhibiting the mevalonate pathway to down-regulate GPX4 expression. In addition, the FA-LDH@SIM group significantly inhibited tumor growth after treatment in the animal glioma model. These results indicate that the FA-LDH@SIM nanodrug delivery system exhibits excellent anti-tumor effects both in vitro and in vivo, and is an effective method for the treatment of glioma.Copyright © 2023. Published by Elsevier Inc.