Exosomal GABPB1-AS1 derived from GA-MSCs inhibits ferroptosis in glioblastoma cells by regulating the SUMOylation of PCBP2

Glioma-associated mesenchymal stem cells (GA-MSCs) are key regulators in the glioblastoma (GBM) microenvironment, enhancing tumor progression through proliferation, angiogenesis, and EMT. While GA-MSCs’ effects via protein-coding genes are well studied, their regulation of GBM via non-coding RNAs and ferroptosis remains poorly understood. This study investigates how GA-MSCs influence ferroptosis in GBM cells through the long non-coding RNA GABPB1-AS1. An in vitro co-culture model and RNA sequencing identified GABPB1-AS1 as GA-MSC–regulated. GABPB1-AS1 knockdown/overexpression experiments were used to assess ferroptosis markers, including Fe²⁺, MDA, glutathione metabolism, and mitochondrial changes. RNA pulldown and mass spectrometry identified PCBP2 as a GABPB1-AS1–interacting protein. Co-immunoprecipitation evaluated the impact on TRIM28–PCBP2 interactions and PCBP2 SUMOylation. Site-directed mutagenesis confirmed TRIM28-mediated SUMOylation sites. GA-MSC–derived exosomes were isolated and characterized; uptake by GBM cells was tracked. An orthotopic xenograft mouse model assessed in vivo tumorigenicity. GA-MSCs increased GABPB1-AS1 expression in GBM cells, suppressing ferroptosis and promoting tumor proliferation. GABPB1-AS1 enhanced TRIM28–PCBP2 interaction, inducing SUMO2/3 modification at PCBP2 K185, stabilizing PCBP2 by preventing ubiquitination. Stabilized PCBP2 bound to FPN1, reducing ferroptosis. GA-MSC–derived exosomes transferred GABPB1-AS1 to GBM cells, enhancing proliferation. In vivo, these exosomes increased tumor volume, shortened survival, and elevated GPX4, PCBP2, and Ki67 levels. GA-MSCs deliver GABPB1-AS1 via exosomes to GBM cells, promoting TRIM28-mediated SUMOylation and stabilization of PCBP2, thereby inhibiting ferroptosis and enhancing GBM progression.