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Peer-reviewedCC BYCells

HSP27 Provides Stress-Adaptive Proteostasis Buffering in Glioblastoma and Is Therapeutically Vulnerable

  • Yuexia Jiao1
  • Qi Liu1
  • Yuchun Zhang1
  • Xiuyuan Wang2
  • Xinjun Liang3,4,5
  • Shaozhong Wei3,4,5
  • Zijian Tang1
5 affiliations
  1. 1College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
  2. 2School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
  3. 3Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
  4. 4Hubei Provincial Clinical Research Center for Colorectal Cancer, Wuhan 430079, China
  5. 5Wuhan Clinical Research Center for Colorectal Cancer, Wuhan 430079, China
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Abstract

Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), remains one of the most aggressive primary brain tumors, and its proteostasis machinery represents a potential therapeutic target. Here we identify HSP27 as a key regulator-associated proteostasis in glioblastoma, IDH-wildtype, where it is linked to protein synthesis, folding, stress-granule dynamics and ubiquitin-mediated turnover. Ribo-seq showed HSP27 depletion reduced global protein synthesis, while TME labeling coupled to mass spectrometry revealed increased accumulation of unfolded proteins, indicating proteotoxic stress. Proteomic analysis of isolated stress granules (SGs) revealed enhanced sequestration of translational regulators, including EIF4E, mTOR, EIF3M and QKI, into stress granules (SGs), thereby reinforcing translational repression. Ubiquitinome profiling further revealed increased ubiquitination and proteasome-dependent loss of oncogenic and translational regulators, including AKT2, PARP1, EIF4G1, EIF4A3, and DDX5. Functionally, targeting HSP27 inhibits tumor growth and sensitizes glioblastoma to translational blockade. In orthotopic models, antisense oligonucleotide targeting HSP27 in combination with Didemnin B suppressed tumor progression and prolonged survival compared with either single agent. These findings associate HSP27 with proteostasis in glioblastoma, IDH-wildtype, and suggest HSP27-dependent proteostasis buffering as a therapeutic vulnerability.

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Cite

BibTeXRIS
BibTeX
@article{jiao2026hsp27,
  title = {{HSP27 Provides Stress-Adaptive Proteostasis Buffering in Glioblastoma and Is Therapeutically Vulnerable}},
  author = {Yuexia Jiao and Qi Liu and Yuchun Zhang and Xiuyuan Wang and Xinjun Liang and Shaozhong Wei and Zijian Tang},
  journal = {Cells},
  year = {2026},
  month = sep,
  doi = {10.3390/cells15191794},
  url = {https://europepmc.org/article/PMC/PMC13664483},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - HSP27 Provides Stress-Adaptive Proteostasis Buffering in Glioblastoma and Is Therapeutically Vulnerable
AU  - Yuexia Jiao
AU  - Qi Liu
AU  - Yuchun Zhang
AU  - Xiuyuan Wang
AU  - Xinjun Liang
AU  - Shaozhong Wei
AU  - Zijian Tang
PY  - 2026
DA  - 2026/09/30
JO  - Cells
DO  - 10.3390/cells15191794
UR  - https://europepmc.org/article/PMC/PMC13664483
AB  - Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), remains one of the most aggressive primary brain tumors, and its proteostasis machinery represents a potential therapeutic target. Here we identify HSP27 as a key regulator-associated proteostasis in glioblastoma, IDH-wildtype, where it is linked to protein synthesis, folding, stress-granule dynamics and ubiquitin-mediated turnover. Ribo-seq showed HSP27 depletion reduced global protein synthesis, while TME labeling coupled to mass spectrometry revealed increased accumulation of unfolded proteins, indicating proteotoxic stress. Proteomic analysis of isolated stress granules (SGs) revealed enhanced sequestration of translational regulators, including EIF4E, mTOR, EIF3M and QKI, into stress granules (SGs), thereby reinforcing translational repression. Ubiquitinome profiling further revealed increased ubiquitination and proteasome-dependent loss of oncogenic and translational regulators, including AKT2, PARP1, EIF4G1, EIF4A3, and DDX5. Functionally, targeting HSP27 inhibits tumor growth and sensitizes glioblastoma to translational blockade. In orthotopic models, antisense oligonucleotide targeting HSP27 in combination with Didemnin B suppressed tumor progression and prolonged survival compared with either single agent. These findings associate HSP27 with proteostasis in glioblastoma, IDH-wildtype, and suggest HSP27-dependent proteostasis buffering as a therapeutic vulnerability.
SN  - 2073-4409
ER  -