Preconditioning with sufentanil confers protective effects in transplantation by attenuating hepatic ischemia-reperfusion injury

Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a significant contributor to liver dysfunction and failure following liver transplantation and hepatic surgical procedures. With the increasing global incidence of end-stage liver disease necessitating transplantation, strategies to mitigate HIRI have become important. Ferroptosis, a regulated form of cell death characterized by iron dependency and lipid peroxidation, has recently been recognized as a pivotal mechanism underlying hepatocellular injury during ischemia-reperfusion events. Emerging evidence suggests that in the context of HIRI, ferroptosis is facilitated by the convergence of iron overload, compromised antioxidant defenses, and excessive generation of lipid reactive oxygen species. Notably, EMP1/p38-mediated ferroptosis in liver sinusoidal endothelial cells directly contributes to hepatocyte damage via activation of the p38 mitogen-activated protein kinase pathway. Consequently, ferroptosis represents a promising therapeutic target for HIRI. Pharmacological inhibition of ferroptosis through modulation of the glutathione peroxidase 4 and cyclic guanosine monophosphate-adenosine monophosphate synthase pathways has been shown to ameliorate liver function. The organ-protective effects of sufentanil, a potent μ-opioid receptor agonist commonly employed for perioperative analgesia, extend beyond its anesthetic properties. Preconditioning with sufentanil appears to regulate ferroptosis by targeting activating transcription factor 3. Additionally, sufentanil downregulates the expression of hypoxia-inducible factor 1-alpha and the long noncoding RNA KCNQ1OT1 in HIRI, counteracting their pathological upregulation. These protective effects are closely associated with the attenuation of oxidative stress through the activation of nuclear factor erythroid 2-related factor 2, modulation of inflammatory responses, and preservation of mitochondrial integrity, all of which are mechanistically linked to the regulation of ferroptosis. This review synthesizes current insights into the role of ferroptosis in HIRI and explores the potential of sufentanil preconditioning in mitigating hepatic injury via ferroptosis-related pathways. The evidence to date suggests that sufentanil may attenuate ferroptosis and improve clinical outcomes in HIRI by modulating oxidative stress and associated signaling pathways. Further research on ferroptosis-targeted therapies, including pharmacological modulation of opioid receptor pathways, shows promise for developing novel interventions that protect the liver from ischemia-reperfusion injury.

Keywords: Hepatic ischemia-reperfusion injury; Liver transplantation; Ferroptosis; Iron metabolism; Lipid peroxidation; Oxidative stress; Hepatocellular injury; Sufentanil

Core Tip: Ferroptosis is critically involved in the pathogenesis of hepatic ischemia-reperfusion injury, primarily through the coordinated disruption of iron homeostasis, lipid peroxidation processes, and antioxidant defense mechanisms. Ferroptosis is characterized by morphological and biochemical features that differentiate it from apoptosis and necrosis; the inhibition of ferroptosis results in the reduction of injury markers, improving liver function in an experimental setting. Beyond its established analgesic properties, sufentanil may confer hepatoprotective effects by modulating pathways associated with ferroptosis. Investigating the interplay between sufentanil and ferroptotic mechanisms could yield valuable therapeutic strategies that enhance clinical outcomes in liver surgery and transplantation.