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Endoplasmic reticulum (ER) stress plays a critical role in pancreatic β cell destruction which leads to the pathogenesis of type 1 diabetes mellitus (T1DM).Vitamin D(VD) has been reported to reduce the risk of T1DM;however,it remains unknown whether VD affects ER stress in pancreatic βcells.In this study,we investigated the role of the active form of VD,1,25-dihydroxyvitamin D3[1,25-(OH)2D3],in ER stress-induced β cell apoptosis and explored its potential mechanism in mouse insulinoma cell line mouse insulinoma 6 (MIN6).The results of cell counting kit-8(CCK8) and flow cytometric analyses showed that 1,25-(OH)2D3 caused a significant increase in the viability of MIN6 cells injured by H2O2.The protein kinase like ER kinase (PERK) sig-nal pathway,one of the most conserved branches of ER stress,was found to be involved in this process.H2O2 activated the phosphorylation of PERK,upregulated the activating tran-scription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression,and subsequently initiated cell apoptosis,which were significantly reversed by 1,25-(OH)2D3 pretreatment.In addition,GSK2606414,a specific inhibitor of PERK,suppressed PERK phosphorylation and reduced the expressions of ATF4 and CHOP,leading to a significant decrease in β cell apoptosis induced by H2O2.Taken together,the present findings firstly demonstrated that 1,25-(OH)2D3 could prevent MIN6 cells against ER stress-associated apoptosis by inhibiting the PERK-ATF4-CHOP pathway.Therefore,our results suggested that 1,25-(OH)2D3 might serve as a potential therapeutic target for preventing pancreatic β cell destruction in T1DM.