# Von Hippel–Lindau/Hypoxia Inducible Factor Axis in Glioblastoma

## TL;DR

This review explains how the pVHL-HIF pathway contributes to the aggressive nature of glioblastoma, a deadly brain tumor.

## Contribution

The paper highlights the pVHL-HIF axis as a key driver of glioblastoma malignancy and summarizes its regulatory mechanisms.

## Key findings

- pVHL is frequently mutated or inactivated in glioblastoma, leading to persistent HIF activation.
- HIF activation promotes tumor growth and angiogenesis in the hypoxic glioblastoma microenvironment.
- The pVHL-HIF axis is proposed as a central target for therapeutic intervention in glioblastoma.

## Abstract

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, characterized by rapid proliferation, extensive vascularization, and resistance to conventional therapies. A feature of the GBM microenvironment is hypoxia, which activates a wide range of adaptive responses orchestrated mainly by the hypoxia-inducible factor (HIF). The Von Hippel–Lindau protein (pVHL) is a central regulator of HIF stability, inducing proteasomal degradation under physiological conditions. However, in GBM, the pVHL is frequently mutated or functionally inactivated by several mechanisms, including microRNA regulation, post-translational modifications, or degradation by specific E3 ubiquitin ligases. This loss of function results in persistent HIF activation, thereby enhancing the oncogenic and pro-angiogenic environment that contributes to the progression and aggressiveness of GBM. This review focuses on the multifaceted roles of the pVHL-HIF axis and proposes it as a key driver of GBM malignancy.