The　effects　of　titanium　dioxide　(TiO2)　nanoparticles　(NPs)　on　the　differentiation　of　neural　stem　cells　are　reported.　Our　findings　indicate　that　TiO2　NPs　lead　to　a　differentiational　tendency　towards　neurons　from　neural　stem　cells,　suggesting　TiO2　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　TiO2　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　phosphotylation,　which　is　negatively　regulated　by　the　protein　kinase　C　epsilon　(PKC　epsilon),　is　demonstrated.　It　is　inferred　that　PKCE　plays　a　pivotal　negative　role　in　the　neuronal　differentiation　of　stem　neural　cells　in　response　to　the　TiO2　NPs　exposure.　(C)　2009　Elsevier　Ltd.　All　rights　reserved.