Hongjun Kang,1 Zhi Mao,1 Yan Zhao,1 Ting Yin,2 Qing Song,1 Liang Pan,1 Xin Hu,1 Jie Hu,1 Feihu Zhou1 1Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, 2Department of Critical Care Medicine, The Centre Hospital of BaoTou, BaoTou, People’s Republic of China Background: Ethyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal-ligation-and-puncture-induced septic mice. Methods: The animals were treated intraperitoneally with 0.2 mL of Ringer’s lactate solution or an equivalent volume of Ringer’s lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers. Results: Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP. Conclusion: The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis. Keywords: sepsis, ethyl pyruvate, energy metabolism, inflammation, reactive oxygen species