In the condition of hepatic ischemia-reperfusion injury, HMGB1 is predominantly released by stressed hepatocytes, which actively secrete HMGB1 into the circulation. After release, HMGB1, as a proinflammatory cytokine, combined with TLR4 was expressed on the surface of hepatocytes or other nonparenchymal cells. NF-κB signal pathway is further activated to promote cytokine release, such as TNF-α and IL-6. Under the stimulation of TNF-α and IL-6, intrinsic pathway of apoptosis is initiated, exhibited as the upregulation of Bax and downregulation of Bcl-2. On the other hand, with the translocation of HMGB1 into cytoplasm from nuclei, HMGB1 competitively combined with Beclin-1 to promote the level of autophagy through representing the site of Bcl-2, which can maintain the inactive status of autophagy. Ethyl pyruvate successfully inhibits the expression and translocation of HMGB1 in stressed cells under the condition of hepatic I/R injury and further downregulates intrinsic pathway of apoptosis and autophagy to ameliorate hepatic I/R injury.