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The central nervous system (CNS) diseases are still a major cause of morbidity and mortality throughout the world,which imposes heavy burden on the development of society.Ethionine is a non-proteinogenic amino acid having similar chemical structure and activity to that of methionine,with which it competes.Previous studies have confirmed that ethionine affects various cellular functions by inhibiting the biosynthesis of proteins,RNA,DNA,and phospholipids,or all of them.The relationship of ethionine with some CNS diseases,including neural tube defects,has been investigated recently.However,the detailed effects of ethionine on the nerve cell bioactivities and the underlying mechanisms have not been fully explored.Herein,we systematically investigated the influences of ethionine on the proliferation,differentiation,and apoptosis of neural stem cells (NSCs) and post-mitotic nerve cells.We demonstrated that ethionine inhibited cell viability by disrupting the balance between proliferation and apoptosis,prevented NSCs from differentiating into neurons and astrocytes,and blocked cell progression from G1 to S phase via reducing cyclin D1 function in nerve cells including NSCs,a mouse hippocampal neuron cell line (HT-22),and a mouse brain neuroma cell line (Neuro-2a).We speculated that the inhibitory effect of ethionine on cell viability and differentiation are associated with increased reactive oxygen species production.Our results also supported the concept that ethionine may be an underlying cause of abnormal folate metabolism-induced CNS diseases.Our findings may provide important direction for the application of abnormal folate metabolism-induced CNS diseases in future NSC-based therapies.