Potential effects of different cell death inhibitors in protecting against ischemia-reperfusion injury in steatotic liver

Liver ischemia-reperfusion injury (IRI) remains a common issue and with the increasing incidence of Nonalcoholic fatty liver disease (NAFLD), which are more sensitive to IRI, it is crucial to explore the possible strategy to alleviate the steatotic liver IRI. Several modes of cell death are involved in hepatocytes and immune cells during hepatic IRI, and the effects of different cell death inhibitors including apoptosis, necroptosis, pyroptosis, and ferroptosis in steatotic liver IRI have not been investigated. We established 70% IRI model on steatotic liver in mice. Apoptosis, necroptosis, pyroptosis and ferroptosis inhibitors were used to evaluate their effects on liver injury, inflammatory response, and immune cell infiltration. Immunofluorescence and immunohistochemical results demonstrated that there were apoptosis, necroptosis, pyroptosis, and ferroptosis in the progression of IRI in steatotic liver. All four types of cell death inhibitors showed protective effects, but ferroptosis inhibitor Fer-1 and pyroptosis inhibitor VX765 exerted better protective effects compared the apoptosis inhibitor Z-VAD and necroptosis inhibitor Nec-1. Further, we found that pyroptosis occurred mainly in macrophages and ferroptosis occured primarily in hepatocytes during steatotic liver IRI. Ferroptosis in heaptocytes and pyroptosis in macrophages are two major cell death types involved in steatotic liver IRI and inhibiting these cell death exerted good protective effects.