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Emerging evidence from clinical and preclinical studies suggests that the imipridone ONC201 is well tolerated and may have some clinical impact in discrete diffuse intrinsic pontine glioma patients (DIPG). A primary goal of our work is to determine if DIPG are uniquely sensitive to ONC201 and if so, whether ONC201 itself can be used as a tool to illuminate novel vulnerabilities in DIPG. To accomplish this, we are utilizing a combination of patient-derived cell lines as well as mouse xenografts that dovetail with a variety of molecular, epigenetic and metabolomic tools. A central finding from our work is that ONC201 primarily activates the mitochondrial protease, ClpP in DIPG patient-derived cell lines, an effect consistent with recently described ONC201 mechanism of action in other tumors. We further demonstrate that activation of ClpP by ONC201 leads to a host of downstream effects in DIPG model systems including distinctive effects on the metabolome leading to direct alterations in the unique epigenetic signature of DIPG. By directly manipulating these metabolic and epigenetic factors we provide prospective mechanistic insight into how ONC201 as well as ClpP activity impacts DIPG growth and tumorigenicity. These preclinical research findings shed light on potential therapeutic vulnerabilities in DIPG as well as ways that these strategies may be combined to enhance their potential.