Background: Liver transplantation is the most effective treatment for end-stage liver disease. However, the shortage of donor livers has become a significant obstacle to the advancement of liver transplantation. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been extensively investigated in liver diseases. However, the underlying mechanisms of how they can protect organ donation after cardiac death (DCD) livers remain unclear.

Methods: In this study, an arterialized mouse non-heart-beating (NHB) liver transplantation model was used to investigate the effect of MSCs-Exo on NHB liver transplantation. The survival rates, histology, pro-inflammatory cytokine and chemokine expression, and underlying mechanisms were investigated.

Results: The infusion of MSCs-Exo reduced the injury to DCD liver graft tissue. In vitro and in vivo experiments demonstrated that MSCs-Exo could inhibit hydrogen peroxide-induced pyroptosis of Kupffer cells. We found that miR-17-5p was significantly abundant in MSCs-Exo, targeting and regulating the TXNIP expression. This action inhibited NLRP3-mediated pyroptosis of Kupffer cells through the classical Caspase1-dependent pathway, alleviating DCD liver graft injury.

Conclusion: Our study elucidated a protective role for MSCs-Exo in a NHB liver transplantation model. This mechanism provides a theoretical basis and new strategies for the clinical application of MSCs-Exo to improve liver graft quality and alleviate the organ shortage in liver transplantation.