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Gastric cancer is a common malignancy worldwide.The occurrence of multidrug resistance(MDR)is the major obstacle for effective gastric cancer chemotherapy.In this study,the in-depth molec-ular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated.The results showed that DJ-1 expression level was higher in MDR variant SGC7901NCR cells than that in its parental SGC7901 cells.Moreover,DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells,while DJ-1 knockdown in SGC7901NCR cells induced re-sensitization to adriamycin,vincristine,cisplatin,and 5-fluorouracil.These results suggested that DJ-1 mediated the develop-ment of MDR in SGC7901 gastric cancer cells.Importantly,further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells.Meanwhile,we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN,consequently resulting in Nrf2 phosphorylation and activation,and thereby inducing Nrf2-dependent P-glycoprotein(P-gp)and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells.Overall,these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells.The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells,prompting its further investigation as a molecular target to overcome MDR.