Stress granules restrain ferroptosis by sequestering ferritin

  • Nat Cell Biol. 2026 Jun;28(6):1204-1218. doi: 10.1038/s41556-026-01953-5.
Zehe Ge  #  1  2 ,  Zihan Wang  #  2 ,  Erjie Zhao  #  2 ,  Yizhuo Guo  #  3 ,  Longxiu Zhang  2 ,  Fuwei Tian  2 ,  Mengdie Li  2 ,  Yunfei Ma  2 ,  Fangshu Ding  2 ,  Liuguijie He  2  4 ,  Shuhong Sun  2 ,  Minfeng Tong  5 ,  Wenxia Xu  6 ,  Xiefeng Wang  7  8 ,  Junxia Zhang  7  8 ,  Lingxiang Wu  9 ,  Yudan Zhang  10 ,  Lili Niu  11 ,  Qianghu Wang  9 ,  Rong Yin  1 ,  Xiao Li  12  13 ,  Yongping You  7  8 ,  Jeremy N Rich  14  15 ,  Xiuxing Wang  4  8 ,  Bing Yao  16 ,  Zhumei Shi  17  18 ,  Zhou Yang  19 ,  Xin Ge  20  21 ,  Fang Liu  22 ,  Bo Chu  23 ,  Xu Qian  24  25  26  27  28  29  30
Affiliations
  • 1. Jiangsu Key Laboratory of Innovative Cancer Diagnosis and Therapeutics, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
  • 3. Digital Intelligence Neural Research Laboratory, Department of Neurosurgery, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, China.
  • 4. Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 5. Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
  • 6. Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
  • 7. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 8. Institute for Brain Tumors, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
  • 9. Department of Bioinformatics, Nanjing Medical University, Nanjing, China.
  • 10. Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 11. Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 12. Department of Urologic Surgery, Jiangsu Cancer Hospital & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
  • 13. Jiangsu Institute of Cancer Research, Jiangsu Cancer Hospital & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
  • 14. University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.
  • 15. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 16. National Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Department of General Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 17. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 18. Institute for Brain Tumors, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 19. Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 20. Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. [email protected].
  • 21. Institute for Brain Tumors, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 22. Digital Intelligence Neural Research Laboratory, Department of Neurosurgery, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, China. [email protected].
  • 23. Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 24. Jiangsu Key Laboratory of Innovative Cancer Diagnosis and Therapeutics, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 25. Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. [email protected].
  • 26. Institute for Brain Tumors, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 27. Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing, China. [email protected].
  • 28. Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, China. [email protected].
  • 29. Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Disease, Nanjing Medical University, Nanjing, China. [email protected].
  • 30. Key Laboratory of Immunoregulation and Intervention for Major Chronic Diseases of Jiangsu Province, Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 42174134 DOI: 10.1038/s41556-026-01953-5
Abstract

Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ through Ferroptosis. The profiling of SG proteins reveals the recruitment of iron-related proteins including ferritin. Mechanistically, G3BP1, an SG core protein, directly interacts with ferritin light chain in an IR/TMZ-induced G3BP1 methionine-333 oxidation-dependent manner. This interaction facilitates recruiting and sequestering ferritin into SGs, thereby restricting Ferroptosis by limiting Fe2+ content in the labile iron pool and preventing ferritinophagy. Disrupting G3BP1 and ferritin light chain binding using a screened small molecule, ciwujianoside C3, mitigates the restriction of SGs on Ferroptosis, and resensitizes GSCs to IR/TMZ in both in vitro and animal models. These findings unveil a negative regulation of SGs on Ferroptosis, and reveal a promising strategy to disrupt the SG-ferroptosis axis for treating glioblastomas and probably Other types of Cancer.

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