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Atractylenolide Ⅲ (ATL-Ⅲ),a sesquiterpene compound isolated from Rhizoma Atractylodis Macrocephalae,has revealed a number of pharmacological properties including anti-inflammatory,anti-cancer activity,and neuroprotective effect.Thisstudy aimed to evaluate the cytoprotective efficiency and potential mechanisms of ATL-Ⅲ on corticosterone injured rat phaeochromocytoma (PC12) cells.Our results demonstrate that ATL-Ⅲ increases cell viability and reduces the release of lactate dehydrogenase (LDH).The results suggest that ATL-Ⅲ protects PC12 cells from corticosterone-induced injury by inhibiting the intracellular Ca2+ overloading,inhibiting the mitochondrial apoptotic pathway and modulating the MAPK/NF-κB inflammatory pathways.These findings provide a novel insight into the molecular mechanism by which ATL-Ⅲ protected the PC 12 cells against corticosterone-induced injury for the first time.Our results provide the evidence that ATL-Ⅲ may serve as a therapeutic agent in the treatment of depression.