Ischemia and reperfusion (I/R)-induced liver injury contributes to morbidity and mortality during hepatic surgery or liver transplantation. As a pivotal regulator of cancer and inflammation, the role of Von Hippel-Lindau (VHL) in hepatic I/R injury remains undetermined.

Thus, we identified the VHL-HIF-1α/HIF-2α axis as an indispensable pathway that may be a novel target for mediating hepatic I/R injury.

We investigated the role of VHL in hepatic I/R injury by generating VHL conditional knockout (VHL-KO) mice. The downstream mechanisms of VHL were confirmed, and the role of HIF-2α in hepatic I/R injury was further investigated.

In this study, we discovered that VHL upregulation was associated with hepatic I/R injury in a mouse model. VHL gene knockout (VHL-KO) and overexpression (Ad-VHL) mice demonstrated that VHL aggravated liver injury, increased inflammation, and accelerated cell death in hepatic I/R injury. The VHL protein (pVHL) regulates a crucial control mechanism by targeting HIFα subunits for ubiquitin-mediated degradation. In vitro and in vivo studies demonstrated that VHL interacted with and repressed hypoxia-inducible factor 1α (HIF-1α) and hypoxia-inducible factor 2α (HIF-2α) expression during hepatic I/R injury. Notably, the inhibition of HIF-1α or 2α, as well as the concurrent inhibition of HIF-1α and 2α, abrogated the protective effect of VHL-KO. The severe stabilization of HIF-1α or 2α, as well as the simultaneous overexpression of HIF-1α and 2α, compensated for the detrimental effect of VHL. Conclusions: Thus, we identified the VHL-HIF-1α/HIF-2α axis as an indispensable pathway that may be a novel target for mediating hepatic I/R injury.