STING-mediated mitochondrial DNA release exacerbates PANoptosis in liver ischemia reperfusion injury

STING, a pentameric transmembrane protein, plays a vital role in regulating the innate immune response to viral and bacterial infections. Recent research has underscored its significance in acute liver injury, yet its involvement in hepatic ischemia-reperfusion injury (HIRI) has not been thoroughly explored. To bridge this knowledge gap, we embarked on a comprehensive study using wild-type mice to investigate STING activation following surgical intervention for HIRI. Our findings revealed that STING was notably activated in wild-type mice after liver ischemia-reperfusion surgery. Conversely, STING-deficient mice demonstrated markedly improved liver function, suggesting a detrimental role for STING in HIRI. To unravel the underlying mechanisms, we conducted in vitro experiments employing hypoxia-reoxygenation (H/R) stimulation. These experiments illuminated that mitochondrial DNA (mtDNA) leakage into the cytoplasm activates STING, subsequently promoting hepatocyte PANoptosis. Mechanistically, we observed an upregulation of PANoptosis proteins in response to STING activation during HIRI. Moreover, we administered IMT1B in vivo to inhibit mtDNA release and found that this intervention effectively blocked STING activation and curbed PANoptosis, thereby safeguarding liver function. Our study comprehensively substantiates that STING senses mtDNA release to induce PANoptosis in hepatocytes, exerting a pivotal role in HIRI. These findings not only offer a fresh perspective on HIRI but also underscore the potential therapeutic benefits of targeting STING or mtDNA release pathways, such as through IMT1B, to enhance liver transplantation outcomes and potentially yield better clinical results for patients undergoing this procedure.