Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury

Summary: Oxygen-dependent preservation has been proposed to protect liver grafts from ischemia-reperfusion injury (IRI), but its underlying mechanism remains elusive. Here, we proposed an oxygen-carrying sequential preservation (OCSP) method that combined oxygenated static cold storage (SCS) and normothermic mechanical perfusion. We demonstrated that OCSP, especially with high oxygen partial pressure level (500–650mmHg) during the oxygenated SCS phase, was associated with decreased IRI of liver grafts and improved rat survival after transplantation. A negative correlation between autophagy and endoplasmic reticulum stress response (ERSR) was found under OCSP and functional studies indicated OCSP suppressed ERSR-mediated cell apoptosis through autophagy activation. Further data showed that OCSP-induced autophagy activation and ERSR inhibition were oxygen-dependent. Finally, activated NFE2L2-HMOX1 signaling was found to induce autophagy under OCSP. Together, our findings indicate oxygen-dependent autophagy mitigates liver graft’s IRI by ERSR suppression and modulates NFE2L2-HMOX1 signaling under OCSP, providing a theoretical basis for liver preservation using a composite-sequential mode.