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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Xiaodong Li,
  • Hongyan Guo,
  • Ziyi Liu,
  • Tianze Wang,
  • Maode Wang,
  • Wei Chen,
  • Hai Yu

摘要

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.