RNA-binding protein WDR4 drives temozolomide resistance and malignant proliferation in glioblastoma by suppressing EEF1A2 translation efficiency to promote metabolic reprogramming

Background Acquired resistance to temozolomide (TMZ) severely limits its therapeutic efficacy in glioblastoma (GBM). The role of WD repeat domain 4 (WDR4) in TMZ resistance remains unclear. This study aims to elucidate the molecular mechanism by which WDR4 regulates TMZ resistance in GBM and to explore its therapeutic potential. Results WDR4 expression is significantly upregulated in TMZ-resistant cells, where it inhibits eukaryotic translation elongation factor 1A2 (EEF1A2) translation efficiency by impairing EEF1A2 mRNA stability. Knockdown of WDR4, particularly in combination with TMZ, significantly suppressed tumor growth in nude mice. WDR4 knockdown also inhibited U251/R cell proliferation, migration, and invasion; induced G0/G1 phase arrest and apoptosis; and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A, hexokinase 2, and pyruvate kinase M2. In addition to modifying the expression of glycolytic enzymes, WDR4 knockdown further led to decreased glucose uptake, reduced lactate production, and lower intracellular ATP levels in U251/R cells. Notably, all the aforementioned effects induced by WDR4 knockdown were reversed when EEF1A2 expression was further knocked down in the same cell model. Conclusions WDR4 promotes TMZ resistance and malignant progression in GBM by facilitating glycolytic reprogramming, which is mediated through the suppression of EEF1A2 translation efficiency via disruption of its mRNA stability.