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  3. PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer

PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer

  • Nat Cell Biol. 2025 Mar 3. doi: 10.1038/s41556-025-01610-3.
Yizeng Fan # 1 2 3,  Yuzhao Wang # 1 2 3,  Weichao Dan # 1 2 3,  Yilei Zhang 4,  Li Nie 5,  Zhiqiang Ma 6,  Yanxin Zhuang 1 2 3,  Bo Liu 1 2 3,  Mengxing Li 1 2 3,  Tianjie Liu 1 2 3,  Zixi Wang 1 2 3,  Leihong Ye 1 2 3,  Yi Wei 1 2 3,  Yuzeshi Lei 1 2 3,  Chendong Guo 1 2 3,  Jiale An 1 2 3,  Chi Wang 1 2 3,  Yulin Zhang 1 2 3,  Jin Zeng 1 2 3,  Wenyi Wei 7,  Boyi Gan 8 9,  Lei Li 10 11 12
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 3 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
  • 4 The Institute of Molecular and Translational Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • 5 State Key Laboratory for Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, China.
  • 6 Department of Medical Oncology, Senior Department of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, Beijing, China.
  • 7 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. wwei2@bidmc.harvard.edu.
  • 8 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bgan@mdanderson.org.
  • 9 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. bgan@mdanderson.org.
  • 10 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. lilydr@163.com.
  • 11 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. lilydr@163.com.
  • 12 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. lilydr@163.com.
  • # Contributed equally.
PMID: 40033101 DOI: 10.1038/s41556-025-01610-3
Abstract

The activation of Ferroptosis has shown great potential for Cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic Ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of Glutathione Peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing Ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 Ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 Inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving Cancer therapy efficacy, by acting to reduce the counteraction of Ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.

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