Abstract

Cancer cells rely on lipogenesis in addition to exogenous lipid uptake, and fatty acid synthase (FASN) is aberrantly overexpressed in myeloid leukemia, yet its role in leukemogenesis is unclear. We show that FASN is essential for leukemogenesis. Its genetic ablation impairs leukemic cell growth, survival, and clonogenicity in vitro , and reduces disease burden in vivo , without significantly affecting normal hematopoiesis. We further identify a platensimycin derivative compound MS-C19 as a potent FASN inhibitor. MS-C19 suppresses growth and clonogenicity in clinical acute myeloid leukemia (AML) samples. Mechanistically, FASN inhibition or deficiency activates lysosomal and inflammatory gene programs, inducing lysosomal membrane permeabilization and associated cell death but not lysosome biogenesis. We further identify that GRN, a lysosomal and neuroinflammatory gene, is potently transcribed by TFEB upon FASN inhibition. GRN depletion reverses the anti-leukemic effects of FASN loss. Our findings establish FASN as a therapeutic target and support its pharmacological inhibition by MS-C19 for leukemia treatment.