PLEKHG2 Drives Glioma Proliferation and Growth <i>via</i> Possible Suppression of the P53 Pathway

<h3>Background/Aim:</h3> Glioma is a prevalent and aggressive central nervous system tumor with a poor prognosis, highlighting the urgent need for novel therapeutic targets. This study aimed to investigate the role of PLEKHG2 in glioma progression, prognosis, and immune infiltration. <h3>Materials and Methods:</h3> We systematically analyzed the expression profile of PLEKHG2 and its clinical relevance in glioma using integrated RNA sequencing data from TCGA cohort. The association between PLEKHG2 expression and clinicopathological features was evaluated. Survival analyses were performed to determine its prognostic value for survival. Gene Set Enrichment Analysis (GSEA) was employed to uncover PLEKHG2-associated biological pathways and immune microenvironment characteristics. The functional role of PLEKHG2 was validated through <i>in vitro</i> knockdown experiments assessing cell proliferation, apoptosis, migration, and invasion, as well as <i>in vivo</i> xenograft tumor models. <h3>Results:</h3> PLEKHG2 was markedly upregulated in glioma tissues and closely correlated with WHO grade, IDH status, and primary therapy outcome. Elevated PLEKHG2 expression likely predicted unfavorable survival. GSEA revealed significant enrichment of PLEKHG2 in cell cycle–related pathways and highlighted its association with specific immune infiltration patterns. Functional assays demonstrated that PLEKHG2 knockdown suppressed glioma cell proliferation, migration, and invasion, and promoted apoptosis <i>in vitro</i>. Consistently, PLEKHG2 knockdown significantly attenuated tumor growth in xenograft models. Mechanistically, the tumor-suppressive effects of PLEKHG2 silencing were linked to p53 pathway activation, as these phenotypes were substantially reversed by p53 inhibition with PFT-α. <h3>Conclusion:</h3> PLEKHG2 is identified as a critical promoter of glioma malignancy, likely functioning through the p53 pathway. PLEKHG2 represents a promising prognostic biomarker and a potential therapeutic target for glioma intervention.