# Enhanced lipid metabolism serves as a metabolic vulnerability to a polyunsaturated fatty acid (PUFA)-rich diet in glioblastoma

## TL;DR

Enhanced lipid metabolism in glioblastoma can be exploited as a vulnerability using a PUFA-rich diet, which may help fight the disease when combined with radiation.

## Contribution

A PUFA-rich diet is proposed as a metabolic vulnerability in glioblastoma, offering a new therapeutic strategy without carbohydrate restriction.

## Key findings

- PUFA-rich diets disrupt lipid homeostasis in glioblastoma cells, causing lipid peroxidation and cytotoxicity.
- The PUFA-rich diet synergizes with radiation therapy to enhance anti-tumor effects in mouse models.
- The diet does not require carbohydrate restriction, potentially improving long-term adherence.

## Abstract

Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and novel approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily translated into clinical application.