HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells PMID: 42234559

ADC Targets in Oncology

2026-04-10

HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells

Cell Rep. 2026 Jun 23;45(6):117490. doi: 10.1016/j.celrep.2026.117490.

Junlei Yang ¹ , Qiankun Lin ² , Danling Gu ³ , Jiancheng Gao ² , Yang Liu ⁴ , Kailin Yang ⁵ , Zhe Zhu ⁶ , Chenfei Lu ⁷ , Daqi Li ² , Shusheng Ci ⁸ , Fan Lin ⁹ , Qianghu Wang ¹⁰ , Xu Qian ¹⁰ , Yongping You ¹¹ , Qigang Zhou ¹² , Xiuxing Wang ¹³ , Ming Lu ¹⁴ , Qian Zhang ¹⁵ , Yun Chen ¹⁶ , Weiwei Tao ¹⁷ , Junxia Zhang ¹⁸

Affiliations

1. Department of Immunology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
2. National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
3. National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214000, China.
4. Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
5. Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
6. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
7. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
8. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China.
9. National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
10. Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
11. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
12. Department of Clinical Pharmacology, School of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
13. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214000, China; Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China.
14. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 211116, China. Electronic address: [email protected].
15. National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: [email protected].
16. Department of Immunology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214000, China; Department of Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
17. College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China. Electronic address: [email protected].
18. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: [email protected].

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) promote radioresistance and therapeutic failure, yet the underlying mechanisms remain unclear. Here, we show that heat shock protein HSPA6 promotes GSC radioresistance by enhancing GTP synthesis. HSPA6 is induced by irradiation and reduces GSC sensitivity to radiotherapy. HSPA6 interacts with and activates IMPDH2, a key rate-limiting enzyme in purine biosynthesis, thereby promoting GTP synthesis, reducing DNA damage, and enhancing radioresistance. Mechanistically, HSPA6 recruits ROCK2 to phosphorylate and activate IMPDH2 at S416. Pharmacological inhibition of HSPA6 and IMPDH2 combined with irradiation significantly improves survival in mice bearing GBM. Our study uncovers the crucial role of HSPA6/IMPDH2-mediated GTP synthesis in GSC radioresistance and suggests that targeting this axis may improve radiotherapy efficacy for GBM.

Keywords

CP: Cancer; CP: Genomics; GTP synthesis; glioblastoma; glioblastoma stem cells; heat shock protein family A member 6; radioresistance.