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Here, a cell signaling\u2010focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. 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