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Objective To investigate whether vascular endothelial growth factor receptor-3 (VEGFR-3)/VEGF-C signaling suppresses activation of Kupffer cells (KCs) and attenuates hepatic ischemia-reperfusion injury (IRI) after liver transplantation. Methods Liver transplantation model was established in 12 pairs of Lewis-Lewis rats, 6 pairs for VEGF-C group and the other for control group. The donor livers of the VEGF-C group were perfused with VEGF-C injection via portal vein during cold preservation, while those of control group were perfused with UW solution. Another 6 rats served as sham operation group. In 24 h after transplantation, all rats were sacrificed, and serum levels of alanine transaminase (ALT), total bilirubin (TBIL) and inflammatory cytokines, as well as histological changes were detected and observed. KCs were isolated from the grafts. RT-PCR was used to evaluate the expression of VEGFR-3 and polarization-specific marker genes, EMSA was utilized to quantify the nuclear factor-κB (NF-κB) transcriptional activity, and Western blotting was employed to assess the expression of suppressor of cytokine signaling 1(SOCS1) and phosphorylated glycogen synthase kinase 3β (p-GSK3β). Results Compared with the controls, VEGF-C perfusion reduced serum ALT and TBIL levels, alleviated liver damage and suppressed the contents of proinflammatory cytokines (P < 0.05), but increased IL-10 level (P < 0.05). The VEGFR-3 mRNA level in KCs was increased after reperfusion in both VEGF-C group and control group (P < 0.05) when compared with the sham operation group (P < 0.05). In KCs, the mRNA levels of M1 specific marker genes and NF-κB activity were significantly inhibited in VEGF-C group (P < 0.05), while the mRNA levels of M2 specific marker genes and the expression of SOCS1 and p-GSK3β were enhanced when compared with control group (P < 0.05). Conclusion Exogenous VEGF-C protects liver graft from IRI by regulating the inflammatory responses and modifying polarization of KCs.