摘要：SummaryThe role of lipid metabolism in human pluripotent stem cells (hPSCs) is poorly understood. We have used large-scale targeted proteomics to demonstrate that undifferentiated hPSCs express different fatty acid (FA) biosynthesis-related enzymes, including ATP citrate lyase and FA synthase (FASN), than those expressed in hPSC-derived cardiomyocytes (hPSC-CMs). Detailed lipid profiling revealed that inhibition of FASN resulted in significant reduction of sphingolipids and phosphatidylcholine (PC); moreover, we found that PC was the key metabolite for cell survival in hPSCs. Inhibition of FASN induced cell death in undifferentiated hPSCs via mitochondria-mediated apoptosis; however, it did not affect cell survival in hPSC-CMs, neurons, or hepatocytes as there was no significant reduction of PC. Furthermore, we did not observe tumor formation following transplantation of FASN inhibitor-treated cells. Our findings demonstrate the importance ofde novoFA synthesis in the survival of undifferentiated hPSCs and suggest applications for FASN inhibition in regenerative medicine.Graphical AbstractDisplay OmittedHighlights•Undifferentiated hPSCs upregulatede novoFA synthesis-related enzymes•Inhibition ofde novoFA synthesis induces cell death in undifferentiated hPSCs•Phosphatidylcholine is the key metabolite required for hPSC survival•FASN inhibition eliminates undifferentiated hPSCs from hPSC derivativesBiological Sciences; Cell Biology; Stem Cells Research; Proteomics; Metabolomics; Metabolic Flux Analysis
