‐15a‐5p Regulates Ferroptosis in Glioblastoma by Targeting

Abstract

ABSTRACT Aims Glioblastoma (GBM) remains the most lethal primary brain tumor, and the molecular mechanisms driving its aggressiveness are incompletely understood. Recent multi‐omics analyses have identified miR‐15a‐5p as one of the core microRNAs most closely associated with GBM. This study aimed to investigate the functional role and mechanism of miR‐15a‐5p in GBM pathogenesis. cns71097-sec-0001 Methods Expression of miR‐15a‐5p was analyzed in GBM tissues and cell lines. Genetic silencing experiments were performed to assess cell proliferation, migration, and tumor growth across multiple GBM cell lines and in an intracranial xenograft model. Ferroptosis‐related changes were evaluated, and target validation was conducted using luciferase reporter assays. Rescue experiments were performed by co‐modulating miR‐15a‐5p and GLS2. cns71097-sec-0002 Results miR‐15a‐5p was significantly overexpressed in GBM tissues and cell lines, and high expression correlated with poor patient survival. Genetic silencing of miR‐15a‐5p suppressed GBM cell proliferation and migration and inhibited tumor growth in vivo. Mechanistically, miR‐15a‐5p directly targeted the 3′UTR of glutaminase 2 (GLS2). Knockdown of miR‐15a‐5p induced ferroptosis‐related features, including GPX4 downregulation, ACSL4 upregulation, iron accumulation, lipid peroxidation, and mitochondrial contraction. These effects were reversed by GLS2 knockdown in both in vitro and in vivo rescue experiments. cns71097-sec-0003 Conclusion The miR‐15a‐5p/GLS2 axis represents a previously unrecognized mechanism by which GBM cells resist ferroptosis. These findings not only define a novel mechanism underlying ferroptosis regulation in GBM but also identify the miR‐15a‐5p/GLS2 axis as a potential entry point for ferroptosis‐based therapeutic intervention. Targeting this axis may provide a rational strategy to modulate ferroptosis and suppress GBM progression. cns71097-sec-0004 Schematic diagram of the mechanism by which miR‐15a‐5p regulates glioblastoma progression through targeting GLS2 and modulating ferroptosis. miR‐15a‐5p regulates the ferroptosis pathway by targeting and inhibiting glutaminase 2 (GLS2) expression: Downregulation of miR‐15a‐5p leads to upregulation of GLS2, which promotes lipid peroxidation, accompanied by elevated levels of ferrous ions (Fe), malondialdehyde (MDA), and acyl‐CoA synthetase long‐chain family member 4 (ACSL4), as well as decreased expression of glutathione peroxidase 4 (GPX4), ultimately inducing ferroptosis in glioblastoma (GBM) cells. Activation of ferroptosis further suppresses the proliferation and migration of GBM cells, reduces tumor volume in tumor‐bearing mice, and thereby blocks the progression of glioblastoma. graphical