Aim: Apoptosis participated in the pathological process of myocardial ischemia/reperfusion (I/R) injury. Previous studies have reported that endogenous substance sRAGE protect against I/R injury through inhibiting myocardial apoptosis. But the mechanisms are currently unknown. Prior work has demonstrated that ubiquitin proteasome system (UPS) dysfunction is closely related to apoptosis. We explored the potential role of UPS in the effect of sRAGE inhibition on I/R-induced myocardial apoptosis. Methods and results: Adult male C57BL mice treated with sRAGE (100 mu g/day, i.p.) or saline were performed to ligate left anterior descending coronary artery (LAD) as an in vivo model. As an in vitro model, primary murine cardiomyocytes pretreated with sRAGE or sRAGE-containing adenovirus were simulated I/R by "ischemia buffer". The TUNEL and caspase-3 activity were assessed. Also the activity and expression of proteasome were detected. sRAGE decreased the number of TUNEL-positive cardiomyocytes and caspase-3 activity, however, the inhibition of sRAGE on I/R-induced apoptosis was abolished by proteasome inhibitor Bortezimb (BTZ). sRAGE inhibited the decreased proteasome activity, also the reduction in protein and gene levels of beta 1i and beta 5i following I/R. Suppression of STAT3 blocked the inhibition of sRAGE on apoptosis induced by I/R. The chromatin immunoprecipitation (CHIP) results confirmed that sRAGE promoted activating STAT3 binding to beta 1i and beta 5i promoter. Conclusions: Our data suggest that the inhibition of sRAGE on I/R-induced apoptosis is associated with activation and expression of proteasome, including improved proteasome activity and elevated beta 1i and beta 5i expression mediated by STAT3 activation. We predict that sRAGE is a novel intervention to target UPS activation for preventing and treating myocardial apoptosis. (C) 2016 Elsevier Inc. All rights reserved.