By combining transcriptomic and proteomic analysis in siEZH2-depleted PAH-PASMCs, we identified disease-relevant functions of EZH2 in maintaining the bioenergetic machinery of oxidative phosphorylation and stimulating expression of genes associated with cell-cycle progression and survival; providing a useful resource that can be exploited to identify new actionable targets to improve pulmonary vascular remodeling in the setting of PAH. Here, EZH2 is linked to pulmonary arterial hypertension.