Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK

Fangzhou Guo; Guoyuan Ling; Jianting Qiu; Jicheng Li; Yu Gan; YingYing Yu; Jiamei Tang; Ligen Mo; Haozhe Piao

doi:10.1186/s13020-024-00920-2

Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK

Chin Med. 2024 Mar 22;19(1):52. doi: 10.1186/s13020-024-00920-2.

Authors

Fangzhou Guo^{1

2}, Guoyuan Ling^{1

2}, Jianting Qiu³, Jicheng Li⁴, Yu Gan⁴, YingYing Yu³, Jiamei Tang⁴, Ligen Mo⁵, Haozhe Piao⁶

Affiliations

¹ Department of Neurosurgery, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, China.
² Graduate School, Dalian Medical University, Dalian, 116044, Liaoning, China.
³ Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang, 110042, Liaoning, China.
⁴ Graduate School, China Medical University, Shenyang, 110042, Liaoning, China.
⁵ Department of Neurosurgery, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, China. moligen@gxmu.edu.cn.
⁶ Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110801, Liaoning, China. piaohaozhe@cancerhosp-ln-cmu.com.

Abstract

Background: Ferroptosis, a non-apoptotic form of cell death induced by accumulation of free iron ions and lipid peroxidation, its importance for cancer treatment is gradually being recognized. Research on the anti-cancer mechanism of juglone is accumulating. However, the specific mechanism by which it directs glioblastoma (GBM) to death is unknown.

Methods: We used in vitro and in vivo experiments to explore the anti-GBM effect generated by juglone through the ferroptosis pathway.

Results: Juglone mainly causes cell death by inducing ferroptosis. Mechanistically, juglone can significantly activate the phosphorylation of p38MAPK. According to transcriptome sequencing and protein interaction analysis, the Nrf2-GPX4 signaling pathway is identified as the primary pathway through which juglone mediates ferroptosis. In vitro and in vivo experiments further verified that juglone induces the ferroptosis of GBM by activating the phosphorylation of p38MAPK and negatively regulating the Nrf2-GPX4 signaling pathway.

Conclusion: Juglone induces ferroptosis and inhibits the growth of GBM by targeting the Nrf2/Gpx4 signaling pathway and thus holds promise as a novel ferroptosis inducer or anti-GBM drug.

Keywords: Ferroptosis; Glioblastoma; Juglone; Nrf2; p38MAPK.