Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China.
Cell Death Dis. 2022 Jun 13;13(6):548. doi: 10.1038/s41419-022-04997-1.
Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its mechanism in gliomas remains elusive. Acyl-coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regulation of lipid biosynthesis, benefits the initiation of ferroptosis, but its role in gliomas needs further clarification. Erastin, a classic inducer of ferroptosis, has recently been found to regulate lipid peroxidation by regulating Acsl4 other than glutathione peroxidase 4 (GPX4) in ferroptosis. In this study, we demonstrated that heat shock protein 90 (Hsp90) and dynamin-related protein 1 (Drp1) actively regulated and stabilized Acsl4 expression in erastin-induced ferroptosis in gliomas. Hsp90 overexpression and calcineurin (CN)-mediated Drp1 dephosphorylation at serine 637 (Ser637) promoted ferroptosis by altering mitochondrial morphology and increasing Acsl4-mediated lipid peroxidation. Importantly, promotion of the Hsp90-Acsl4 pathway augmented anticancer activity of erastin in vitro and in vivo. Our discovery reveals a novel and efficient approach to ferroptosis-mediated glioma therapy.
铁死亡是一种新发现的受调控的细胞死亡（RCD）形式，其特征是铁依赖性脂质活性氧（ROS）的积累，但它在神经胶质瘤中的机制仍不清楚。酰基辅酶 A（CoA）合成酶长链家族成员 4（Acsl4）是脂质生物合成调节的关键酶，有利于铁死亡的启动，但它在神经胶质瘤中的作用需要进一步阐明。新型铁死亡诱导剂 erastin 最近被发现通过调节 Acsl4 而不是谷胱甘肽过氧化物酶 4（GPX4）来调节铁死亡中的脂质过氧化。在这项研究中，我们证明热休克蛋白 90（Hsp90）和与动力蛋白相关的蛋白 1（Drp1）在 erastin 诱导的神经胶质瘤铁死亡中主动调节和稳定 Acsl4 的表达。Hsp90 过表达和钙调神经磷酸酶（CN）介导的 Drp1 在丝氨酸 637（Ser637）去磷酸化促进铁死亡，改变线粒体形态并增加 Acsl4 介导的脂质过氧化。重要的是，促进 Hsp90-Acsl4 途径增强了 erastin 在体外和体内的抗癌活性。我们的发现揭示了一种新的有效的铁死亡介导的神经胶质瘤治疗方法。
