胶质母细胞瘤（GBM）是最常见的原发性颅内肿瘤，对常规临床化疗高度耐药。最近，诱导铁死亡正在成为治疗各种肿瘤的假定策略。然而，有效且适用的肿瘤铁死亡诱导剂的鉴定仍然具有挑战性。在这项研究中，我们发现长卡乌林 A (LK-A) 是一种从药用植物 Isodon ternifolius 中分离出来的天然二萜类化合物，具有很强的抗 GBM 能力，可诱导显着的 GBM 细胞铁死亡，同时抑制关键的抗铁死亡因子谷胱甘肽过氧化物酶 4（ GPX4）。 GPX4 启动子包含保守的 CpG 岛。 LK-A 诱导的 GPX4 抑制与 10-11 易位 2 (TET2)（一种关键的 DNA 去甲基化酶）的抑制以及 GPX4 启动子高甲基化的增加同时发生。此外，在皮下和原位异种移植小鼠模型中，LK-A 促进 GBM 铁死亡改变并抑制 GBM 进展，而 GPX4 过表达在体外和体内很大程度上消除了其抗 GBM 作用，表明 LK-A 诱导 DNA 甲基化-引起的 GPX4 抑制和铁死亡对其抗 GBM 功能至关重要。我们的研究共同阐述了 GBM 铁死亡的重要表观遗传途径，并揭示了 LK-A 治疗 GBM 患者的关键药理学特性。版权所有 © 2024。由 Elsevier B.V. 出版。

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients.Copyright © 2024. Published by Elsevier B.V.