Purpose Mü ller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions. The objective of this study was to determine the potential mechanism of Mü ller cell proliferation and VEGF production due to high-glucose conditions. Methods Primary cultured rat Mü ller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h. The proliferation of Mü ller cells was assessed by the MTT assay. The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array. Results High concentrations of glucoseinduced Mü ller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1a, NFkB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis. However, Mü ller cell alterations induced by highglucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/ phosphorylations (out of 47) were restored to their normal levels. Nine proteins, including NFkB p65, p-p38, tumor necrosis factor-a, urokinase-type plasminogen activator, CREB, IL-1b, HCAM, estrogen receptor-a, and p-Stat3, were involved in regulatory networks between XIAP and VEGF. Conclusions The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Mü ller cells. Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy.