FASN LINKS MITOCHONDRIAL REMODELING AND NEUROGENESIS IN HUMAN NSCS AND CEREBRAL ORGANOIDS

Human brain development requires tight coordination between metabolic supply and neurogenic program. De novo lipogenesis (DNL), catalyzed by fatty acid synthase (FASN), generates endogenous fatty acids for complex lipid synthesis and fuels mitochondrial β-oxidation and tricarboxylic acid (TCA) cycle activity. Although FASN-dependent lipogenesis and mitochondrial function are both essential for neural stem cell (NSC) biology, how these pathways are integrated during human neurodevelopment remains poorly defined. In this study, we suppressed FASN in hiPSC-derived NSCs by siRNA-mediated knockdown and in three-dimensional human cerebral organoids by pharmacological inhibition, and we analyzed the resulting changes using confocal microscopy, bioenergetic profiling, lipidomics, RNA sequencing, and electron microscopy.
In NSCs, our data showed that FASN inhibition reduced mitochondrial membrane potential and oxygen consumption, lowered ATP production, and increased mitochondrial reactive oxygen species, indicating impaired mitochondrial bioenergetics. These defects were accompanied by dysregulated β-oxidation and glycolytic parameters, enlarged mitochondrial networks, increased triacylglycerol and neutral lipid droplets, and glycogen-like cytoplasmic accumulations. Transcriptomic profiling revealed selective modulation of pathways linked to lipid metabolism, mitochondrial organization, glucose metabolism, and neural differentiation. In cerebral organoids, FASN inhibition decreased proliferative NSC/progenitor pools, reduced ventricular zone size, and shifted the balance toward premature neuronal differentiation, with disrupted cortical-like layering.
Together, these findings identify FASN as a key regulator of mitochondrial function, metabolic homeostasis, and neurogenic dynamics in human neural systems. The integration of human NSC cultures with cerebral organoids provides a human-relevant framework that links lipogenesis to mitochondrial remodeling and cortical organization, with implications for metabolic contributions to neurodevelopmental disorders.