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Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Nat Commun. 2022-03; 
Nian Jiang, Bowen Xie, Wenwu Xiao, Ming Fan, Shanxiu Xu, Yixin Duan, Yamah Hamsafar, Angela C Evans, Jie Huang, Weibing Zhou, Xuelei Lin, Ningrong Ye, Siyi Wanggou, Wen Chen, Di Jing, Ruben C Fragoso, Brittany N Dugger, Paul F Wilson, Matthew A Coleman, Shuli Xia, Xuejun Li, Lun-Quan Sun, Arta M Monjazeb, Aijun Wang, William J Murphy, Hsing-Jien Kung, Kit S Lam, Hong-Wu Chen, Jian Jian Li
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摘要

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A, CPT2, ACAD9 cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 ... More

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