Acylglycerol Kinase Sensitizes Glioblastoma to Temozolomide via Limiting Mitochondrial Damage Related Cellular Senescence

Temozolomide (TMZ) is still the first-line drug for glioblastoma (GBM) treatment though tumor cell resistance remains a major challenge. TMZ administration may induce cellular senescence (CSEN), which exerts a dual regulatory effect on tumor progression, and evidence has suggested that CSEN is closely associated with mitochondrial dysfunction. Acylglycerol kinase (AGK), a mitochondrial membrane kinase, has been reported to participate in regulating mitochondrial function and the production of reactive oxygen species (ROS). Here, we aimed to investigate the role of AGK in GBM progression and TMZ resistance, assessed whether CSEN mediates these effects, and investigated the therapeutic potential of senolytic agents. Firstly, the analysis of TCGA data revealed that the increased expression of AGK was correlated with a poor prognosis of GBM patients. Secondly, through cell experiments of AGK-knockdown and overexpression, we found that AGK suppression inhibited the proliferation of tumor cells while paradoxically promoting TMZ resistance. Mechanistically, AGK suppression amplified TMZ-induced CSEN through increasing mitochondrial ROS (mtROS) and decreasing membrane potential. Conversely, Mito-TEMPO, a mtROS scavenger, and FOXO4-DRI, a senolytic agent, both enhanced the therapeutic efficacy of TMZ by eliminating these senescent cells via apoptosis. Furthermore, the clinical analysis linked AGK levels, CSEN, and prognosis of GBM patients treated with TMZ. In conclusion, our results establish senescence induction as a novel mechanism for AGK-mediated TMZ sensitization, suggesting that co-targeting AGK and CSEN represents a promising strategy to enhance TMZ therapy.