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Background & Aims The hallmarks of hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, include severe cell death and inflammatory responses that contribute to early graft failure and a higher incidence of organ rejection. Unfortunately, effective therapeutic strategies are limited. Tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 transduces apoptosis and/or inflammation-related signaling pathways to regulate cell survival and cytokine production. However, the role of TRAF3 in hepatic I/R-induced liver damage remains unknown. Methods Hepatocyte- or myeloid cell-specific TRAF3 knockdown or transgenic mice were subjected to an I/R model in vivo , and in vitro experiments were performed by treating primary hepatocytes from these mice with hypoxia/reoxygenation stimulation. The function of TRAF3 in I/R-induced liver damage and the potential underlying mechanisms were investigated through various phenotypic analyses and biological approaches. Results Hepatocyte-specific, but not myeloid cell-specific, TRAF3 deficiency reduced cell death, inflammatory cell infiltration, and cytokine production in both in vivo and in vitro hepatic I/R models, whereas hepatic TRAF3 overexpression resulted in the opposite effects. Mechanistically, TRAF3 directly binds to TAK1, which enhances the activation of the downstream NF-κB and JNK pathways. Importantly, inhibition of TAK1 almost completely reversed the TRAF3 overexpression-mediated exacerbation of I/R injury. Conclusions TRAF3 is a novel hepatic I/R mediator that promotes liver damage and inflammation via TAK1-dependent activation of the JNK and NF-κB pathways. Inhibition of hepatic TRAF3 may represent a promising approach to protect the liver against I/R injury-related diseases. [ABSTRACT FROM AUTHOR]