Oxidative　stress　leads　to　melanocyte　death　and　has　been　implicated　in　the　pathogenesis　of　vitiligo.　The　nuclear　factor,　E2-related　factor　2　(Nrf2),　is　a　critical　transcription　factor　in　protecting　cells　from　oxidative　damage.　High-mobility　group　box　1　(HMGB1)　is　a　chromatin-associated　nuclear　protein　and　an　extracellular　damage-associated　molecular　pattern　molecule.　Extracellular　HMGB1　released　from　activated　immune　cells,　necrotic　or　injured　cells,　becomes　a　proinflammatory　mediator　through　binding　to　cell-surface　receptors　of　responding　cells.　In　this　study,　we　investigated　the　role　of　HMGB1　from　melanocytes　in　the　response　to　oxidative　stress　and　the　mechanism　involved.　We　showed　that　HMGB1　is　expressed　by　primary　normal　human　epidermal　melanocytes　(NHEMs).　H＜sub＞2＜/sub＞　O＜sub＞2＜/sub＞　treatment　increased　cytoplasmic　translocation　and　extracellular　release　of　HMGB1.　HMGB1　knockdown　by　small　interfering　RNA　(siRNA)　led　to　decreased　apoptosis　of　NHEMs.　HMGB1　inhibition　enhanced　the　expression　of　Nrf2　and　its　target　genes.　The　expression　of　Nrf2　and　its　downstream　antioxidant　genes　was　downregulated　after　the　supernatant　of　H＜sub＞2＜/sub＞　O＜sub＞2＜/sub＞　-treated　NHEMs　was　added　to　HMGB1-deficient　cells.　HMGB1　knockdown　by　siRNA　suppressed　the　expression　of　the　autophagosome　marker,　LC3,　and　enhanced　p62　expression.　Coimmunoprecipitation　with　Keap1　showed　a　reduced　Nrf2-Keap1　interaction　and　an　increased　p62-Keap1　interaction　under　oxidative　stress.　These　data　demonstrated　that　external　stimuli　(eg,　oxidative　stress)　may　trigger　autocrine　HMGB1　translocation　and　release　by　melanocytes,　suppressing　the　expression　of　Nrf2　and　downstream　antioxidant　genes　to　induce　melanocyte　apoptosis,　and　thereby　participate　in　the　pathological　process　of　vitiligo.