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 limited therapeutic options. Dysregulation of FXYD5 has been reported in multiple malignancies, suggesting FXYD5 as a potential target for precision medicine. In the present study, FXYD5 expression and prognostic significance were analyzed using biological analysis on multiple databases and it was identified that FXYD5 was observably upregulated in GBM and inversely correlated with the prognosis of patients. Functional studies were investigated in LN229 and U251 GBM cell lines through FXYD5 knockdown and overexpression approaches, assessing proliferation (Cell Counting Kit‑8), apoptosis (flow cytometry), migration/invasion (Transwell assays) and lipid metabolism (free fatty acids, triglycerides, cholesterol, Nile Red staining). Knockdown of FXYD5 suppressed GBM cell proliferation, migration and invasion, while increasing apoptosis, indicating that FXYD5 may serve as a therapeutic target for GBM. Mechanistic studies examined the PI3K/AKT/long‑chain acyl‑coenzyme A (CoA) synthase 4 4 (ACSL4) pathway via western blotting and rescue experiments, finding that FXYD5 activated the PI3K/AKT signaling pathway, leading to upregulation of ACSL4 and enhanced lipid metabolism. In vivo, a subcutaneous xenograft mouse model was used to evaluate whether PI3K/AKT inhibition could antagonize FXYD5 overexpression‑induced tumor growth and PI3K/AKT inhibition reversed FXYD5 overexpression‑induced tumor growth in the subcutaneous mouse model. These findings revealed that FXYD5 promotes GBM progression via the PI3K/AKT/ACSL4 signaling axis and represents a potential therapeutic target for GBM.