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The aim of the present study was to investigate the protective effects and underlying mechanisms of Garcinia xanthochymus,a perennial medicinal plant native to Yunnan,China,against H2O2-induced oxidative damage in rat pheochromacytoma PC12 cells.Preincubation of PC12 cells with fruit EtOAc fraction (fruit-EFr.,12.5-50 μmol·L-1) of G.xanthochymus for 24 h prior to H2O2 exposure markedly improved cell viability and increased the activities of antioxidant enzymes (superoxide dismutase,catalase,and heme oxygenase-1 [HO-1]),prevented lactate dehydrogenase release and lipid peroxidation malondialdehyde production,attenuated the decrease of matrix metalloproteinases (MMP),and scavenged reactive oxygen Species (ROS).Fruit-EFr.also reduced BAX and cytochrome C expression and improved BCL-2 expression,thereby decreasing the ratio of BAX to BCL-2.Fruit-EFr.activated the nuclear translocation of NRF2 to increase HO-1 and induced the phosphorylation of AKT.Its cytoprotective effect was abolished by LY294002,a specific inhibitor of PI3K.Taken together,the above findings suggested that fruit-EFr.of G.xanthochymus could enhance cellular antioxidant defense capacity,at least in part,through upregulating HO-1 expression and activating the PI3K/AKT pathway and that it could suppress H2O2-induced oxidative damage via PI3K/AKT and NRF2/HO-1 signaling pathways.