The effects of titanium dioxide (TiO(2)) nanoparticles (NPs) on the differentiation of neural stem cells are reported. Our findings indicate that TiO(2) NPs lead to a differentiational tendency towards neurons from neural stem cells, suggesting TiO(2) NPs might be a beneficial inducer for neuronal differentiation. To insight into the possible molecular mechanism of the neuronal differentiation, we conducted a protein-protein interaction network (PIN) analysis. To this end, a global mapping of target proteins induced by TiO(2) NPs was first made by a 2-dimensional electrophoresis analysis. Results showed that 9 proteins were significantly changed and then they were subjected to the mass spectrometric assay. All 9 identified proteins are involved in signal, molecular chaperones, cytoskeleton, and nucleoprotein. Further, based on our experimental data and DIP, IntAct-EBI, GRID database, a protein-protein interaction network was constructed, which provides highly integrated information exhibiting the protein-protein interaction. By analysis of the gene expression, the signal pathway involving Cx43 phosphorylation, which is negatively regulated by the protein kinase C epsilon (PKCepsilon), is demonstrated. It is inferred that PKCepsilon plays a pivotal negative role in the neuronal differentiation of stem neural cells in response to the TiO(2) NPs exposure.