MYCN amplification is found in 25% of neuroblastoma patients and it is consistently associated with treatment failure and poor prognosis. Cancer cells undergo metabolic reprogramming that allows them to maintain a high rate of macromolecular synthesis, essential for cell growth and division. Most of the studies in the field of cancer metabolism are focused on aerobic glycolysis (the "Warburg effect") and a high dependence on glutamine. However, other important pathways such as lipid metabolism have been less extensively addressed. c-MYC has been strongly related to tumor metabolism as a potent activator of both glycolysis and glutaminolysis, but not much has been described about the role of MYCN in these processes. Our group performs pioneering research in the area of neuroblastoma metabolism. We previously demonstrated that MYCN downregulation not only triggers neural differentiation but also accumulation of neutral lipids (Zirath et al PNAS, 2013). Silencing of MYCN or targeting the protein with small molecule inhibitors prompt changes in lipid metabolism due to reduced ß-oxidation and mitochondrial dysfunction. The lipid accumulation is accompanied by morphological changes and expression of neural differentiation markers. Now, we further investigated the relationship between lipid metabolism and neuroblastoma cell differentiation. The chemical inhibition of de novo fatty acid synthesis (targeting either acetyl-CoA carboxylase, ACC, or fatty acid synthese, FASN) triggers MYCN protein downregulation and differentiation of both MYCN-amplified and non-amplified neuroblastoma cells. Importantly, the inhibition of ACC, but not of FASN, impairs accumulation of lipid droplets and downregulates mitochondrial respiration depending on MYCN protein levels. Cell membrane-permeable fatty acids do not prevent the phenotypes observed, suggesting that they are mediated by means other than fatty acid depletion. Our work aims to elucidate the impact of lipid metabolism on neuroblastona biology, with potential implications for metabolism-targeted and differentiation-based therapies.