Pathophysiological mechanisms of cell death affecting graft survival in liver transplantation.

Abstract

Early allograft dysfunction (EAD) is a significant complication of liver transplantation (LT). LT remains the sole curative treatment for patients with end-stage liver disease. EAD is correlated with heightened morbidity, extended stays in intensive care units, and decreased graft survival rates. Within the clinical practice, EAD presents a substantial challenge, necessitating vigilant monitoring, heightened clinical awareness, and prompt multidisciplinary intervention to prevent progression to primary graft nonfunction and multiorgan failure. Multiple forms of programmed cell death, including necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, PANoptosis, and NETosis, have been implicated in graft injury. Apoptosis facilitates the regulated elimination of damaged or senescent hepatocytes via caspase-dependent pathways, whereas necroptosis and other necrotic mechanisms exacerbate caspase-independent tissue injury through membrane disruption and the release of inflammatory mediators. Pyroptosis, driven by inflammasome activation and gasdermin-mediated pore formation, further amplifies inflammatory signaling within the graft. Moreover, ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a pivotal contributor to hepatocellular injury during hepatic ischemia-reperfusion events. Failure of hepatocellular protective mechanisms to adequately counteract energy depletion and oxidative stress during ischemia results in cell death, which subsequently activates immune and contributing to acute graft rejection.