2. Academic Validation
  3. Deciphering the STAT3-PXN positive feedback loop in GBM, IDH-wildtype: transcriptional regulation and inhibition of YB-1 ubiquitination

Deciphering the STAT3-PXN positive feedback loop in GBM, IDH-wildtype: transcriptional regulation and inhibition of YB-1 ubiquitination

  • Cell Death Discov. 2026 Mar 23;12(1):168. doi: 10.1038/s41420-026-03035-9.
Xiaodong Li # 1 2 3 4,  Hongyan Guo # 1 2,  Ziyi Liu 1 2,  Tianze Wang 1 2,  Maode Wang 5 6,  Wei Chen 7,  Hai Yu 8 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi, China.
  • 4 Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, China.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 6 Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 7 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 8 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 9 Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • # Contributed equally.
PMID: 41872167 DOI: 10.1038/s41420-026-03035-9
Abstract

Glioblastoma (GBM) is the most fatal primary brain malignancy in adults, with a median survival of approximately 15 months. The 2021 WHO classification redefined GBM as exclusively IDH-wildtype based on its characteristic molecular and clinical features. In this study, we aimed to identify key prognostic genes in GBM, IDH-wildtype. Using univariate COX proportional hazards regression analysis, PXN was identified as a critical upregulated gene in GBM, IDH-wildtype, significantly associated with poor prognosis. Its expression was further validated by qRT-PCR, western blotting, and immunohistochemistry. Functional assays revealed that elevated PXN enhances GBM malignancy, whereas its knockdown suppresses corresponding malignant features. Mechanistically, PXN and STAT3 form a positive feedback loop: STAT3 upregulates PXN transcription, and PXN, in turn, activates STAT3 by regulating Src transcription. Additionally, PXN stabilizes YB-1 protein by inhibiting its ubiquitination. Further mRNA Sequencing analysis demonstrated that YB-1 contributes to maintaining GBM malignancy through multiple signaling pathways. These results suggest that the STAT3-PXN positive feedback axis and the regulation of YB-1 stability by PXN may offer novel targets for GBM therapy. PXN is elevated in GBM, IDH-wildtype and associated with poor prognosis and malignant features. STAT3 directly promotes PXN transcription, and PXN reciprocally activates STAT3 by regulating Src transcription. PXN stabilizes YB-1 protein by inhibiting its ubiquitin-mediated degradation.

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