In recent years, a particular interest has focused on the accumulation of fatty acids with very long chains (VLCFA) in the occurrence of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis or dementia. Indeed, it seems increasingly clear that this accumulation of VLCFA in the central nervous system is accompanied by a progressive demyelination resulting in death of neuronal cells. Nevertheless, molecular mechanisms by which VLCFA result in toxicity remain unclear. This study highlights for the first time in 3 different cellular models (oligodendrocytes 158 N, primary mouse brain culture, and patient fibroblasts) the types of cell death involved where VLCFA-induced ROS production leads to autophagy. The autophagic process protects the cell from this VLCFA-induced toxicity. Thus, autophagy in addition to oxidative stress can offer new therapeutic approaches. Display omitted •VLCFA induce cell death, whose early events are not associated with apoptosis/necrosis.•VLCFA induce reactive oxygen species production and activation of antioxidant defences.•Changes in relocation and aggregation of lysosomes with VLCFA treatment.•Autophagy protect against toxicities induced by VLCFA.•DHA counteract VLCFA-induced toxicity.