Glioblastoma (GBM), the most common form of primary central nervous system tumors, has long been inherently difficult to treat and has been impossible to cure. These difficulties can be attributed to the presence of Glioma stem cells (GSCs) within the tumor and their innate ability to drive tumor progression, growth, and recurrence. Examining the metabolic activity, particularly that of fatty acids (FAs), in GSCs serves as a novel therapeutic approach to establishing new methods of treatment. 

After knockdown of SCD1, it was found that tumor propagation was halted altogether, reinforcing GSC dependability on lipid synthesis. Pharmacological inhibition of SCD1 using a highly potent small-molecule inhibitor of SCD1 achieved a strong therapeutic outcome in two GSCs mouse models and was able to cure several mice bearing brain tumors. SCD1 is primarily localized in the endoplasmic reticulum (ER), and Fatty acids are known to impact ER stress thus hinting at a direct link between SCD1 activity and ER stress. Indeed, we report that the inhibition of SCD1 activity causes a toxic accumulation of Saturated fatty acids which cause an overwhelming ER stress response, therefore, promoting apoptotic cell death in GSCs. 

In summary, our study demonstrates an essential role for FAs in GSCs maintenance and tumor initiation. We provide preclinical evidence for targeting lipid synthesis pathways in GSCs using potent inhibitors of SCD1 as a therapeutic treatment for GBM.