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We have previously reported that Cystatin C (CysC) is a pivotal mediator in the neuroprotection induced by hyperbaric oxygen (HBO) preconditioning;however,the underlying mechanism and how CysC changes after stroke are not clear.In the present study,we demonstrated that CysC expression was elevated as early as 3 h after reperfusion,and this was further enhanced by HBO preconditioning.Concurrently,LC3-Ⅱ and Beclin-1,two positive-markers for autophagy induction,exhibited increases similar to CysC,while knockdown of CysC blocked these elevations.As a marker of autophagy inhibition,p62 was downregulated by HBO preconditioning and this was blocked by CysC knockdown.Besides,the beneficial effects of preserving lysosomal membrane integrity and enhancing autolysosome formation induced by HBO preconditioning were abolished in CysC-/-rats.Furthermore,we demonstrated that exogenous CysC reduced the neurological deficits and infarct volume after brain ischemic injury,while 3-methyladenine partially reversed this neuroprotection.In the present study,we showed that CysC is biochemically and morphologically essential for promoting autophagic flux,and highlighted the translational potential of HBO preconditioning and CysC for stroke treatment.