Objective: Sepsis is a whole-body inflammation disease and can result in septic shock and multiple organ failure. The previous study demonstrated that miR-27a plays a critical role in inflammation regulation. Here, we investigated that effect and its possible mechanism of rhTNFR:Fc on sepsis treatment. Methods: LPS induced sepsis mice model was established. 10 mg/kg rhTNFR:Fc Was used to treat sepsis mice by intravenous injection. Results: RhTNFR:Fc improved cardiac function of sepsis mice, and markedly decreased miR-27a but increased Nrf2 expression level of myocardium in LPS treated mice. In H9C2 cells, rhTNFR:Fc also increased Nrf2 expression, elevated cell viability and decreased cell apoptosis. However, the effects were reversed by miR-27a mimic. In addition, miR-27a mimic reduced the activity of Nrf2 3'UTR while miR-27a inhibitor elevated enhanced its level. Conclusion: rhTNFR:Fc activated Nrf2 pathway to protect myocardium against LPS-induced sepsis injury via miR-27a regulation. (C) 2015 Elsevier Inc. All rights reserved.