For a study, researchers sought to discover a novel synthetic lethal interaction between ClpP activation and HDAC1/2 inhibition that affects GBM energy metabolism. In patient-derived xenograft (PDX) models of GBM, transcriptome, metabolite, and U-13C-glucose tracing analyses were used. In vivo studies were conducted using orthotopic GBM models. Investigators found that activating the mitochondrial ClpP protease with mutant ClpP (Y118A) or using second-generation imprisoned compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2, as well as global (panobinostat) or selective (romidepsin) HDAC inhibitors, resulted in a synergistic reduction of viability in GBM model systems, which was mediated by interference with tricarbox This effect was partially mediated by apoptosis as well as caspase activation, which Bcl-xL and Mcl-1 primarily regulated. ClpP protease knockdown or ectopic expression of a ClpP D190A mutant significantly rescued from the inhibition of oxidative energy metabolism and the reduction of cell viability caused by ClpP activators and the combination treatment, respectively. Finally, using GBM PDX models, the study group demonstrated that the combination treatment of HDAC inhibitors and imprisons outperformed single treatments or vehicles in vivo. These findings suggested that ClpP activators may significantly enhance the efficacy of HDAC inhibitors in human GBM model systems.