Mechanistic insights into PABPC5-mediated regulation of apoptosis in glioma pathophysiology.

Glioma, especially high-grade gliomas like glioblastoma, are aggressive and highly treatment-resistant brain tumors with poor prognosis. Despite advances in therapeutic strategies, the mechanisms driving glioma progression remain inadequately understood, with dysregulated apoptosis playing a central role in malignancy. RNA-binding proteins(RBPs) such as the poly(A)-binding protein family, including PABPC5, have gained attention due to their roles in regulating mRNA stability and translation. PABPC5’s role in glioma pathogenesis remains poorly characterized despite its identification as a key regulator of the mitochondria-associated programmed cell death index (mtPCDI) in low-grade glioma (LGG). This study thoroughly investigated the oncogenic functions of PABPC5. TCGA-GBM analysis revealed significant decreasing trend in PABPC5 expression with increasing glioma grade(G2 vs. G3:P < 0.05; G2vsG4: P < 0.0001;). However, immunohistochemistry and Western blotting demonstrated that PABPC5 protein levels were elevated in Grade 4 tumors compare to Grades 1–3. Notably, expression levels showed no correlation with overall survival (P = 0.92). Lentiviral infection of PABPC5 knockdown in glioblastoma cells (U87/U251) significantly suppressed malignant phenotypes while inducing pro-apoptotic molecular alterations: upregulated BAX and cleaved caspase−3 protein expression, enhanced ROS production, and reduced Bcl−2 and caspase−3 levels. In vivo validation showed that PABPC5 knocdown substantially inhibited subcutaneous tumor growth and increased apoptosis (TUNEL:3.164-fold increase,P < 0.001). Consistent with in vitro findings, immunofluorescence(IF)analysis of tumor tissues confirmed altered Bcl−2/cleaved-caspase−3 expression patterns and mitochondrial ultrastructural changes. This work establishes PABPC5 as a novel biomarker for glioma pathological grading and reveals its functional role in apoptosis regulation. These findings provide a mechanistic foundation for developing therapeutic strategies targeting apoptosis-resistant glioma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33448-y.