Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - Mediated GPX4 suppression
- Eur J Pharmacol. 2024 Dec 5:984:177061. doi: 10.1016/j.ejphar.2024.177061.
- 1. Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, China; Yancheng Medical Research Center of Nanjing University Medical School, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China.
- 2. Yancheng Medical Research Center of Nanjing University Medical School, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China.
- 3. Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, China.
- 4. Yancheng Medical Research Center of Nanjing University Medical School, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China; Nanjing University Medical School, Jiangsu Key Lab of Molecular Medicine, Nanjing, China. Electronic address: [email protected].
- 5. Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, China; Yancheng Medical Research Center of Nanjing University Medical School, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China. Electronic address: [email protected].
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.