2. Academic Validation
  3. Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4

Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4

  • Cell Death Dis. 2024 Oct 5;15(10):729. doi: 10.1038/s41419-024-06963-5.
Xiangrui Meng # 1 2,  Zixuan Wang # 3 4,  Qingqing Yang 2,  Yawei Liu 1 2,  Yisu Gao 1,  Hefei Chen 2,  Ang Li 2,  Rongqing Li 5,  Jun Wang 6,  Guan Sun 7 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, 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 Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Nanjing, China.
  • 4 Postgraduate College, Xuzhou Medical University, Xuzhou, China.
  • 5 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
  • 6 Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China. wangjun19890630@163.com.
  • 7 Department of Neurosurgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China. sunguan2008@sina.com.
  • 8 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. sunguan2008@sina.com.
  • # Contributed equally.
PMID: 39368999 DOI: 10.1038/s41419-024-06963-5
Abstract

Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream Cancer treatment strategy, with Ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing Ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor Glutathione Peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced Ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in Ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits Ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular Complement Receptor C5aR1 suppresses Ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

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