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

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.