Met-Exo attenuates pyroptosis in miniature pig liver IRI by improving mitochondrial quality control

Metformin(Met) and adipose-derived stem cell exosomes(ADSCs-Exo) both demonstrate therapeutic effects on mitochondrial dysfunction and pyroptosis. There is also a phenomenon of mutual promotion between these two pathological states. The synergistic effect of metformin-loaded exosomes (Met-Exo) via electroporation in a miniature pig liver ischemia-reperfusion injury (IRI) model remains unexplored. This study established a liver IRI model in miniature pigs to compare the effects of ADSCs-Exo and Met-Exo. We found that Met-Exo intervention better activated the Adenosine 5'-monophosphate activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1(SIRT1) axis, improved mitochondrial dynamics, promoted mitochondrial biogenesis, and inhibited the sustained excessive autophagy of mitochondria after liver IRI. It was then demonstrated that by improving mitochondrial dysfunction, ATP production in liver tissue could be ensured, and ROS generation could be suppressed. This also further inhibited the occurrence of pyroptosis and ensured that mitochondria were protected from gasdermin D-N(GSDMD-N) attack. Met-Exo inhibited the occurrence of pyroptosis through the above pathways, reducing the release of inflammatory factors such as IL-1β and IL-18, and alleviating inflammation. This provides a new therapeutic approach for clinical treatment of liver IRI and improving the success rate of liver transplantation.