The total hepatic ischemia/reperfusion injury (IRI) involves the fact that both liver and gut are subjected to warm ischemia, which is a complex unavoidable process encountered during liver transplantation and a serious threat to graft outcome. The ways to improve hepatic IRI are currently limited. The aim of the present study was to explore the protective effect of simvastatin on total hepatic IRI and examine the underlying mechanisms.

Male Sprague Dawley rats were subjected to total (100%) hepatic warm ischemia to induce hepatic IRI. Thirty-six male rats (250–300 g) were randomly divided into three groups: sham, IRI control and simvastatin (1 mg/kg) pretreatment 0.5 h before surgery. Serum samples and liver tissues were collected after reperfusion at 6 and 24 h for further studies.

Simvastatin pretreatment significantly decreased the values of the transaminases alanine aminotransferase and aspartate aminotransferase and improved histological alterations according to improved Suzuki's Score (P < 0.05). Moreover, simvastatin upregulated the expression of Kruppel-like factor 2 (KLF2), phosphorylated endothelial nitric oxide synthase and thrombomodulin (P < 0.05). Furthermore, simvastatin pretreatment affected superoxide dismutase and malondialdehyde activities (P < 0.05) to reduce oxidative stress, and inhibited levels of high-mobility group box-1, CD68, toll-like receptor 4, tumor necrosis factor α, interleukin-1β and interleukin-6 (P < 0.05) to suppress inflammatory response.

Simvastatin pretreatment ameliorates total hepatic IRI via a KLF2-mediated protective mechanism. Simvastatin may be used as a potential prophylactic treatment strategy for clinical trials against hepatic IRI.