Oncogene RPP25 Promotes Glioblastoma Progression by Inhibiting Ferroptosis and Oxidative Stress

Abstract

Background: Glioblastoma (GBM) are the most prevalent malignant brain tumors with extensive morphological and genetic heterogeneity. The objective of this study was to investigate the role of the oncogene Ribonuclease P/MRP Subunit P25 (RPP25) in GBM progression and its underlying molecular mechanisms. Methods: Glioma cell lines were used to evaluate the effects of RPP25 on ferroptosis-related proteins, oxidative stress levels, and reactive oxygen species (ROS) content. In addition, GBM mouse models were established, including an RPP25 overexpression group (OE-RPP25) and an RPP25 overexpression with integrin beta-8 (ITGB8) knockdown group (OE-RPP25+sh-ITGB8). Tumor volume and weight were measured to assess tumor growth. The levels of ferroptosis and oxidative stress were also evaluated using lipid peroxidation and ROS content assays. Results: It was observed that RPP25 overexpression significantly elevated both tumor volume and weight (p < 0.05) compared to the control group. However, when ITGB8 was knocked down in the OE-RPP25 group, tumor volume and weight were reduced. Furthermore, RPP25 overexpression upregulated the expression of ITGB8, hypoxia-inducible factor (FIH1), and glutathione peroxidase 4 (GPX4), while ITGB8 knockdown reversed these effects. Additionally, RPP25 overexpression suppressed the expression of apoptosis-related proteins B-cell lymphoma-2 associated X (Bax) and Caspase-3 and increased (p < 0.05) the expression of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). However, ITGB8 knockdown promoted apoptosis in tumor cells by counteracting these effects. Moreover, RPP25 overexpression inhibited ferroptosis and oxidative stress, while ITGB8 knockdown reversed these effects, promoting lipid peroxidation and glutathione depletion. Conclusions: These findings suggest that RPP25 plays a crucial role in GBM progression by upregulating the ITGB8/transforming growth factor-beta (TGF-β)/Smad4 axis, inhibiting ferroptosis and oxidative stress, and suppressing apoptosis. These findings provide important insights into the interaction between RPP25 and ITGB8 and their potential applications in GBM therapy. Targeting the RPP25-ITGB8 axis may represent a promising strategy for the treatment of GBM by modulating ferroptosis and apoptosis pathways. The findings also suggest that ferroptosis and oxidative stress may be potential targets for GBM therapy.