FXYD5 promotes the growth of glioblastoma by targeting the PI3K/AKT/ACSL4 signaling axis

Abstract Glioblastoma (GBM) is the most malignant primary brain tumor, with few therapeutic therapy options. Abnormalities of FXYD5 have been reported in multiple malignancies, which proposes FXYD5 as a potential target for precision treatment. Here, we identified that FXYD5 was observably upregulated in GBM and inversely correlated with the prognosis of patients. Functional studies showed that the knockdown of FXYD5 suppressed GBM cell growth and progression in vitro, demonstrating that FXYD5 could be the target of GBM treatment. Through bioinformatic analysis, we found FXYD5 was associated with lipid metabolism and the PI3K/AKT signaling pathway. Mechanistically, knockdown of FXYD5 inhibited the activation of the PI3K/AKT signaling pathway, leading to suppression of the expression of lipid metabolism-related gene ACSL4 and level of lipid metabolism. Our study has shown that FXYD5 facilitates GBM progression and metastasis via the PI3K/AKT/ACSL4 signaling axis. Notably, inhibition of PI3K/AKT signal pathway could antagonize FXYD5 overexpression-induced subcutaneous tumorigenesis enlargement in the GBM mouse model. These findings revealed that FXYD5 was a potential therapeutic target in GBM.