Targeting fatty acid metabolism in glioblastoma
Jason Miska, Navdeep S. Chandel
Jason Miska, Navdeep S. Chandel
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e163448. https://doi.org/10.1172/JCI163448.
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Review Series

Targeting fatty acid metabolism in glioblastoma

Abstract

Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.

Authors

Jason Miska, Navdeep S. Chandel

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Figure 2

Perturbing FA catabolism in GBM.

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Perturbing FA catabolism in GBM. FA catabolism is the process by which l...
FA catabolism is the process by which lipids are broken down to generate energy and other metabolic intermediates for cells. This is a tightly controlled process, as too much FA oxidation (FAO) can be toxic to cells. For example, in lipid-rich environments glioma cells have a mechanism by which they store excess FAs/cholesterol in lipid droplets. Under conditions of bioenergetic stress, FAs are liberated from these droplets to provide a robust source of ATP via FAO. The blockade of lipid droplet formation using strategies that targeted various steps (green) caused erroneous mitochondrial FAO resulting in accumulation of ROS and cell death in brain tumors. The bringing of FAs into the mitochondria is controlled by the essential enzyme CPT1 (the CPT1A isoform is rate limiting). Many studies have used genetic and pharmacologic inhibition of CPT1A and have shown broad antitumor activities. Ketone bodies are both a by-product of FAO and a way to transport energy in an intercellular fashion. The protective or deleterious role of ketones in brain tumors is still not clear and is a hotly debated topic in the field of FA metabolism.