Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens and and identified the histone chaperone nucleophosmin 1 ( ) as a potential therapeutic target. Genetic ablation of significantly attenuated tumor progression and . Furthermore, -mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support as a therapeutic vulnerability in NSCLC. SIGNIFICANCE: Epigenome-wide CRISPR knockout screens identify as a novel metabolic vulnerability and demonstrate that targeting is a new therapeutic opportunity for patients with NSCLC.