RBM7 suppresses mitochondrial dysfunction and ferroptosis by destabilizing FBXL16 mRNA to enhance Temozolomide...

Temozolomide (TMZ) resistance is a major cause of treatment failure in glioblastoma (GBM). This study investigates the role and mechanism of the RNA-binding protein RNA-binding motif protein 7 (RBM7) and F-box and leucine-rich repeat protein 16 (FBXL16) in TMZ resistance in GBM, focusing on mitochondrial dysfunction and ferroptosis. TMZ-resistant GBM cell lines (TR/U87) were established through gradient induction. Cell viability and proliferation were assessed using the Cell Counting Kit-8 assay and colony formation assays. Western blot analysis and immunohistochemistry were performed to measure FBXL16, activating transcription factor 4, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein expression. Transwell assays evaluated TR/U87 cell migration and invasion. Co-immunoprecipitation and RNA immunoprecipitation assays verified the interaction between RBM7 and FBXL16. An actinomycin D assay analyzed FBXL16 mRNA stability. Flow cytometry was used to detect reactive oxygen species, iron levels, and apoptosis. A nude mouse xenograft model was used to validate in vivo effects. RBM7 was highly expressed in TMZ-resistant cells. Knockdown of RBM7 suppressed TR/U87 cell proliferation and migration, induced mitochondrial structural damage, and triggered ferroptosis. Mechanistically, RBM7 interacted with FBXL16 and reduced its mRNA stability. FBXL16 knockdown reversed RBM7 deficiency-induced ferroptosis and chemosensitivity. In vivo experiments confirmed that RBM7 knockdown combined with TMZ significantly inhibited tumor growth. RBM7 promotes TMZ resistance by suppressing mitochondrial dysfunction and ferroptosis through destabilization of FBXL16. Targeting the RBM7-FBXL16 axis may represent a novel strategy to overcome GBM chemoresistance.