We employed multi-omics approaches combined with in vitro experiments to uncover a novel regulatory mechanism of RUNX1 in GBM, demonstrating that RUNX1 interacted with NPM1 to promote chromatin accessibility and H3K4me3 modification, enhancing FOSL2-mediated transcriptional activation of ECM-related genes, ultimately leading to the ECM remodeling in GBM. The gene discussed is FOSL2; the disease is glioblastoma.