Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade. [Display omitted] •Fatty acid synthase inhibition impairs physiological and pathological angiogenesis•FASN inhibition selectively reduces endothelial cell proliferation, not migration•By elevating malonyl-CoA levels, FASN inhibition promotes mTOR lysine malonylation•The resultant decrease in mTORC1 kinase activity contributes to angiogenic defects Bruning et al. report that blocking fatty acid synthase (FASN) in endothelial cells (ECs) reduces angiogenesis by impairing EC proliferation. Mechanistically, FASN inhibition elevates the malonyl-CoA substrate pool, thereby increasing post-translational malonylation of mTOR and decreasing the pro-angiogenic mTORC1 activity.