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

## TL;DR

This study identifies a feedback loop involving STAT3 and PXN in a specific type of brain cancer, which could lead to new treatment strategies.

## Contribution

The study reveals a novel STAT3-PXN feedback loop and PXN's role in stabilizing YB-1 in IDH-wildtype GBM.

## Key findings

- PXN is upregulated in IDH-wildtype GBM and linked to poor prognosis and malignancy.
- STAT3 and PXN form a positive feedback loop that enhances GBM progression.
- PXN stabilizes YB-1 by inhibiting its ubiquitination, contributing to GBM malignancy.

## 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.

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.