Hepatic ischemia reperfusion injury: Understanding the little components of the larger picture

Abstract

Hepatic ischemia reperfusion injury is especially relevant in the field of liver surgery and transplantation. In the most severe cases, significant liver dysfunction and liver failure can occur, resulting in death or re-transplantation. The mechanisms are complex; however, the most basic concept is that the restoration of blood flow to an ischemic organ can lead to an inflammatory response. The mechanisms that trigger this immune response are not completely understood; however, multiple factors were found to contribute. These include the release of inflammatory cytokines/chemokines, hepatocellular apoptosis, and oxidative stress. Multiple studies, mainly animal models, have examined the potential for various therapies, including pharmacotherapy, to ameliorate ischemia-reperfusion injury. The study by Kelleni et al recently published in the recent issue of the World Journal of Hepatology examines the potential hepatoprotective effect of aprepitant, an antiemetic agent commonly used for nausea related to chemotherapy. In an animal model of ischemia-reperfusion injury, the authors found improved inflammatory markers and survival in rats treated with aprepitant. There have been multiple animal models suggesting various pharmacotherapies to reduce the severity of ischemia-reperfusion injury. The use of aprepitant is unique as it is currently available for use in humans, although further data is needed, side effects need to be monitored, and significant drug interactions could occur.

Key Words: Surgical complications; Liver allograft; Hepatocellular injury; Ischemia prevention; Organ preservation

Core Tip: Despite advancements in surgical techniques and preservation, hepatic ischemia-reperfusion injury (H-IRI) remains a critical hurdle in liver transplantation, contributing to early allograft dysfunction. While machine perfusion represents a major macro-level advancement, pharmacological strategies targeting specific molecular pathways remain an important avenue for mitigating H-IRI. This editorial briefly outlines the complexity of H-IRI mechanisms, discusses emerging pharmacological and mechanical interventions, and highlights recent findings on the neurokinin-1 receptor antagonist aprepitant as a potential therapeutic agent.

This editorial refers to “Targeting sirtuin 1/nuclear factor erythroid 2-related factor 2/tumor necrosis factor-α pathway to modulate hepatic ischemia reperfusion-induced injury” by Kelleni et al, 2025; https://doi.org/10.4254/wjh.v17.i12.110733.

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INTRODUCTION

Hepatic ischemia-reperfusion injury (H-IRI) is a common and clinically significant complication of liver surgery, especially liver transplantation. Mechanistically, H-IRI is driven by mitochondrial dysfunction, oxidative stress, and profound energy depletion, which together trigger hepatocyte death through apoptotic and necrotic pathways[1]. As the name suggests, H-IRI develops after restoration of perfusion to the liver after an ischemic period caused during surgery. Upon reperfusion, the release of damage-associated molecular patterns activates Kupffer cells and recruits neutrophils and monocyte-derived macrophages, which together amplify inflammation and propagate tissue injury[1]. This type of injury is especially notable during liver transplant surgery. Collectively, these interconnected processes manifest as clinically detectable graft injury in the post-transplant setting. In a cohort of 506 liver transplant recipients, histologic H-IRI was present in 87.4% of grafts, and moderate-to-severe injury occurred in 13.8%[2]. Importantly, increasing H-IRI severity was associated with higher rates of early allograft dysfunction (EAD) and reduced 6-month graft survival[2]. H-IRI is also linked to the development of post-transplant biliary complications, which carry significant morbidity and mortality[3].

A large body of experimental research has examined the molecular pathways that both cause and mitigate H-IRI, leading to the opportunity for pharmacologic intervention[1]. Although many pharmacologic agents have demonstrated benefit in animal models, no drug has yet been universally adopted into clinical guidelines for routine prevention of H-IRI in liver transplantation. Machine perfusion technologies have markedly advanced the field by improving organ preservation and enabling more reliable use of higher-risk grafts. However, as the transplant community increasingly relies on marginal or extended-criteria donor livers, which exhibit heightened susceptibility to H-IRI, there remains a compelling need to explore targeted strategies that further mitigate H-IRI and expand the safe utilization of these grafts.

INVESTIGATIONAL PHARMACOLOGIC THERAPIES FOR H-IRI

Preclinical studies have demonstrated that a variety of pharmacological agents can attenuate H-IRI by targeting factors such as mitochondrial stability, oxidative stress, and/or innate immune activation[1]. Examples include select anesthetics, hypoxia-inducible factor activators, immunosuppressants, and antioxidants such as N-acetylcysteine[4-6]. A recent preclinical study of the World Journal of Hepatology by Kelleni et al[7] highlights the therapeutic promise of the anti-emetic aprepitant, a neurokinin-1 receptor antagonist with broad anti-inflammatory, antioxidant, and anti-apoptotic properties. In a rat model of warm H-IRI, aprepitant pretreatment produced dose-dependent improvements across several mechanistic domains of injury. It significantly reduced hepatocellular damage (lower aminotransferase levels), mitigated oxidative stress by lowering malondialdehyde concentrations, and attenuated inflammatory signaling through suppression of tumour necrosis factor alpha and interleukin-6. Aprepitant also reduced caspase-3 activation and enhanced expression of sirtuin-1 and nuclear factor erythroid 2-related factor 2, suggesting coordinated modulation of mitochondrial homeostasis, redox balance, and apoptosis. These pleiotropic effects, together with improvements in histologic injury and overall survival, support further exploration in future studies. However, key questions remain, including optimal dosing, timing (donor, perfusion, or recipient phases), feasibility of administration, and possible drug-drug interactions. In addition, preclinical H-IRI models do not fully capture the immunologic complexity, donor comorbidities, and perioperative variables inherent to human liver transplantation, reinforcing the need for staged translational validation before clinical application.

Beyond animal models, clinical evaluation of pharmacologic strategies to mitigate H-IRI remains limited. A recent randomized clinical trial in the liver transplantation setting tested a multistep, nine-agent regimen that included oral antioxidants, an ex-situ epoprostenol flush, and perioperative anti-inflammatory and cytoprotective agents[6]. Despite the mechanistic rationale, the intervention did not improve peak aminotransferase levels or the rate of EAD, nor did it reduce ischemic cholangiopathy or graft loss over 12 months of follow-up[6]. These findings highlight the difficulty of translating complex, downstream pharmacologic approaches into clinical benefit and underscore the growing rationale for prioritizing upstream graft-conditioning strategies within modern preservation techniques.

THE ROLE OF MACHINE PERFUSION

Machine perfusion has reshaped liver preservation by reducing the magnitude and duration of ischemia and thereby limiting the downstream cascade of H-IRI. Unlike static cold storage, which imposes prolonged hypoxia and promotes mitochondrial dysfunction, perfusion strategies maintain oxygen delivery, support aerobic metabolism, and blunt the oxidative burst that occurs at reperfusion[1]. These mechanistic advantages are particularly relevant for donation after cardiac death (DCD) grafts, which are inherently more susceptible to ischemic injury. An increasingly adopted perfusion approach, normothermic regional perfusion, restores in situ oxygenated circulation after circulatory arrest[1]. Normothermic machine perfusion (NMP) maintains the liver ex situ at physiologic temperatures, preserving aerobic metabolism and allowing real-time functional viability testing before transplantation[8]. In contrast, hypothermic oxygenated perfusion offers a simpler, lower-cost alternative focused on early mitochondrial reoxygenation at low temperatures, limiting succinate accumulation and attenuating reactive oxygen species formation during reperfusion[1].

Clinical data increasingly support the benefits of these technologies. In a recent clinical cohort, NMP significantly reduced EAD, particularly among DCD grafts[9]. In this study, EAD decreased from 50% with static cold storage to 17.5% with NMP[9]. Additional clinical benefits included reduced transfusion requirements, shorter hospital and intensive care unit stays, and lower one-year graft failure risk (by nearly 80% overall, and 87% in DCD grafts)[9]. Likewise, a recent randomized clinical trial evaluating hypothermic oxygenated perfusion demonstrated reductions in EAD, biliary complications, and re-transplantation rates in DCD transplantation[10]. As machine perfusion becomes increasingly integrated into clinical practice, it also presents a unique translational opportunity: The delivery of targeted pharmacologic agents directly to a metabolically active graft within a controlled perfusion environment. Whether such perfusion-based therapeutic strategies provide additive or synergistic protection against H-IRI remains an important question for future investigation.

CONCLUSION

H-IRI is an important factor in surgical outcomes, particularly in transplant programs that increasingly rely on ECD and DCD grafts. Mechanistic insights from preclinical work continue to highlight promising targets, yet clinical translation remains limited. At the same time, advances in machine perfusion have improved early graft performance and expanded the safe utilization of marginal organs. Looking ahead, integration of these two approaches may offer the greatest opportunity for progress. Pharmacologic agents delivered systemically or within the controlled environment of perfusion could provide additional protection, although questions regarding optimal timing, cellular targets, and feasibility remain. Studies such as the one by Kellini et al[7] provide a potential framework for future clinical trials in settings such as liver transplantation.