AbstractIntroductionSjögren's disease (SjD) is a chronic autoimmune disease characterized by the loss of the secretory function of the exocrine glands. At present, drugs that can both correct the immune imbalance and improve exocrine gland function are needed. Meanwhile, vasoactive intestinal peptide (VIP) has been reported as a candidate with anti‐inflammatory and immunoregulatory properties for treating autoimmune diseases.MethodsNonobese diabetic (NOD) mice and the primary splenic lymphocyte cells (SPLCs) were used to construct the SS model. The therapeutic effects of VIP for SjD by evaluating water consumption, histopathology, T cell subsets, and related cytokines. RT‐qPCR and Western blot analysis were used to identify the expression of the PTEN/PI3K/AKT pathway.ResultsWe found that VIP therapy in NOD mice could increase the expression of PTEN and VIP/VPAC1 receptor, as well as decrease the PI3K/AKT pathway. In vitro, the results showed that the PTEN knockdown decreased the Treg/Th17 ratio and enhanced the phosphorylated PI3K/AKT pathway, which were reversed with VIP treatment.ConclusionsVIP exerts potential therapeutic action in SjD by upregulating PTEN through the PI3K/AKT pathway and Treg/Th17 cell balance.