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

Junlei Yang; Qiankun Lin; Danling Gu; Jiancheng Gao; Yang Liu; Kailin Yang; Zhe Zhu; Chenfei Lu; Daqi Li; Shusheng Ci; Fan Lin; Qianghu Wang; Xu Qian; Yongping You; Qigang Zhou; Xiuxing Wang; Ming Lu; Qian Zhang; Yun Chen; Weiwei Tao; Junxia Zhang

doi:10.1016/j.celrep.2026.117490

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

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

Junlei Yang, Qiankun Lin, Danling Gu, Jiancheng Gao, Yang Liu, Kailin Yang, Zhe Zhu, Chenfei Lu, Daqi Li, Shusheng Ci, …

Cell reports (Cambridge), Vol.45(6), 117490

06/23/2026

DOI: 10.1016/j.celrep.2026.117490

PMID: 42234559

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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. [Display omitted] •The upregulated expression of HSPA6 drives radioresistance of GSCs•HSPA6 in GSCs resists radiation by regulating GTP synthesis•HSPA6 recruits protein kinase and ROCK2 and maintains tetramer formation of IMPDH2•The combination of MMF and montelukast enhances the efficacy of radiotherapy against GBM Yang et al. show that irradiation-induced HSPA6 recruits ROCK2 and maintains tetramer formation of IMPDH2, a key rate-limiting enzyme in purine biosynthesis, which in turn promotes GTP synthesis and reduces DNA damage to drive radioresistance of GSCs. Targeting HSPA6 and IMPDH2 may improve the efficacy of radiotherapy for GBM.

glioblastoma

glioblastoma stem cells

GTP synthesis

heat shock protein family A member 6

radioresistance

Details

Title: Subtitle: HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells
Creators: Junlei Yang - Nanjing Medical University
Qiankun Lin - Jiangsu Cancer Hospital
Danling Gu - Nanjing Medical University
Jiancheng Gao - Jiangsu Cancer Hospital
Yang Liu - Nanjing University of Chinese Medicine
Kailin Yang - Cleveland Clinic
Zhe Zhu - Columbia University Irving Medical Center
Chenfei Lu - Nanjing Medical University
Daqi Li - Jiangsu Cancer Hospital
Shusheng Ci - First Affiliated Hospital of Bengbu Medical College
Fan Lin - Nanjing Medical University
Qianghu Wang - Jiangsu Cancer Hospital
Xu Qian - Jiangsu Cancer Hospital
Yongping You - Jiangsu Cancer Hospital
Qigang Zhou - Nanjing Medical University
Xiuxing Wang - Nanjing Medical University
Ming Lu - Nanjing Medical University
Qian Zhang - Jiangsu Cancer Hospital
Yun Chen - Wuxi People's Hospital
Weiwei Tao - Huazhong Agricultural University
Junxia Zhang - Jiangsu Cancer Hospital
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.45(6), 117490
DOI: 10.1016/j.celrep.2026.117490
PMID: 42234559
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: Elsevier Inc
Grant note: National Natural Science Foundation of China: 82072779, 82403427, 82403657 Jiangsu Provincial Key Research Development Program of China: BE2022770 China Postdoctoral Science Foundation: 2023M741795 Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center: T32CA094186 ASCO Conquer Cancer Foundation RSNA Research Fellow Grant
We thank the animal core facility of Nanjing Medical University for its help with animal experiments. This work was supported by the National Natural Science Foundation of China (82072779 to X.W, 82403427 to D.G., and 82403657 to S.C.) , Jiangsu Provincial Key Research Development Program of China (BE2022770 to Y.C.) , and China Postdoctoral Science Foundation (2023M741795 to D.G.). K.Y. was supported by the Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center (T32CA094186) and the Young Investigator Award in Glioblastoma from ASCO Conquer Cancer Foundation, and RSNA Research Fellow Grant.
Language: English
Date published: 06/23/2026
Academic Unit: Radiation Oncology
Record Identifier: 9985174495302771

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