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Objective: To investigate the neuroprotective roles and mechanisms of DcR1 and DcR2 under ischemia and hypoxia.Methods: SH-SY5Y cell were used to build to oxygen glucose deprivation model (OGD) and ischemic preconditioning model (IPC) in vitro. CCK-8 and LDH were performed to evaluate cellular survival and cytotoxicity. Overexpressing DcR1, DcR2 and DR5 were induced by lentivirus vectors, knocking down DcR2 was conducted by siRNA technique in SHSY5Y cells. TRAIL Recombiant Human Protein was employed to activate the TRAIL induced extrinsic apoptotic pathway. Western blot was performed to evaluate the protein level of DcR1, DcR2, DR5, DR4, cleaved caspase-8, cleaved caspase-3 and tBid. Co-immunoprecipitation was used to investigate the interaction of DcR1, DcR2, DR5, DR4, TRAIL and caspase-8. Western blot was performed to evaluate the protein level of pAkt, and LY294002 was used to inhibit the activation of PI3K-Akt pathway.Results: We found that IPC ameliorated the cellular apoptosis and cytotoxicity (P < 0.01), reduced the protein level of DR5 (P < 0.05) and DR4 (P < 0.01), and upregulated the protein level of DcR2 (P < 0.05) after OGD. Besides, overexpressing DcR1 enhanced the protective effect of IPC to cells (P = 0.045, P = 0.01), and knocking down DcR2 abated the protective effect of IPC (P = 0.012, P=0.011) against OGD. Additionally, overexpressing DcR1 or knocking down DcR2 regulated expression of extrinsic apoptosis pathway related proteins, including caspase-8, cleaved caspase-3 and tBid. We also found that overexpressing DcR1 competitively combined TRAIL, suppressed DISC from assembling, and subsequently reduced extrinsic cellular apoptosis. Moreover, we discovered that overexpressing DcR2 inhibited the extrinsic apoptotic pathway via interacting with the extracellular domains of DR5, and up-regulated pAkt (P = 0.0081).Conclution: (1) DcR1 competitively bound with TRAIL, inhibited DISC assembling, and subsequently reduced extrinsic cellular apoptosis. (2) DcR2 inhibited the extrinsic apoptotic pathway via interacting with extracellular domains of DR5. (3) Besides with inhibiting TRAIL, overexpressing DcR2 exerted neuron protection by activating PI3K/Akt pathway.