Complication Of Liver Transplantation Research Articles

Clinical case of staged treatment of combined complications of orthotopic liver transplantation

Hepatic artery thrombosis (HAT) following liver transplantation (LT) is a severe life-threatening complication that can lead to graft loss and mortality after LT. According to different reports, HAT incidence ranges from 2% to 9%. Modern endovascular and radiosurgical techniques allow for minimally invasive liver graft revascularization. Nonetheless, a major consequence of even a successful revascularization is ischemic cholangiopathy, which can lead to ischemic biliary strictures and anastomotic leak. The paper presents a clinical case of long-term complex treatment of combined complications of LT using minimally invasive endovascular and endoscopic techniques.

Donor graft METTL3 gene transfer ameliorates rat liver transplantation ischemia-reperfusion injury by enhancing HO-1 expression in an m6A-dependent manner

Ischemia-reperfusion injury (IRI) is one of the most common complications in liver transplantation. METTL3 regulates inflammation and cellular stress response by modulating RNA m6A modification level. Here, the study aimed to investigate the role and mechanism of METTL3 in IRI after rat orthotopic liver transplantation. The total RNA m6A modification and METTL3 expression level was consistently down-regulated after 6 h or 24 h reperfusion in OLT, which is negatively associated with the hepatic cell apoptosis. Functionally, METTL3 pretreatment in donor significantly inhibited liver grafts apoptosis, improved liver function and depressed the proinflammatory cytokine/chemokine expression. Mechanistically, METTL3 inhibited apoptosis of grafts via upregulating HO-1. Moreover, m6A dot blot and MeRIP-qPCR assay revealed that METTL3 promoted HO-1 expression in an m6A-dependent manner. In vitro, METTL3 alleviated hepatocytes apoptosis by upregulating HO-1 under hypoxia/reoxygenation condition. Taken together, these findings demonstrate that METTL3 ameliorates rat OLT-stressed IRI by inducing HO-1 in an m6A-dependent manner, highlighting a potential target for IRI in liver transplantation.

Effect of the Non-steroidal Anti-inflammatory Drug Diclofenac on Ischemia-Reperfusion Injury in Rat Liver: A Nitric Oxide-Dependent Mechanism.

Ischemia/reperfusion injury (IRI) is an inevitable complication of liver surgery and transplantation. The purpose of this study was to examine the beneficial effects of diclofenac on hepatic IRI and the mechanism behind it. Wistar rats' livers were subjected to warm ischemia for 60min followed by 24h of reperfusion. Diclofenac was administered intravenously 15min before ischemia at 10, 20, and 40mg/kg body weight. To determine the mechanism of diclofenac protection, the NOS inhibitor L-Nitro-arginine methyl ester (L-NAME) was administered intravenously 10min after diclofenac injection (40mg/kg). Liver injury was evaluated by aminotransferases (ALT and AST) activities and histopathological analysis. Oxidative stress parameters (SOD, GPX, MPO, GSH, MDA, and PSH) were also determined. Then, eNOS gene transcription and p-eNOS and iNOS protein expressions were evaluated. The transcription factors PPAR-γ and NF-κB in addition to the regulatory protein IκBα were also investigated. Finally, the gene expression levels of inflammatory (COX-2, IL-6, IL-1β, IL-18, TNF-α, HMGB-1, and TLR-4) and apoptosis (Bcl-2 and Bax) markers were measured. Diclofenac, at the optimal dose of 40mg/kg, decreased liver injury and maintained histological integrity. It also reduced oxidative stress, inflammation, and apoptosis. Its mechanism of action essentially depended on eNOS activation rather than COX-2 inhibition, since pre-treatment with L-NAME abolished all the protective effects of diclofenac. To our knowledge, this is the first study demonstrating that diclofenac protects rat liver against warm IRI through the induction of NO-dependent pathway. Diclofenac reduced oxidative balance, attenuated the activation of the subsequent pro-inflammatory response and decreased cellular and tissue damage. Therefore, diclofenac could be a promising molecule for the prevention of liver IRI.

Doppler-ultrasound reference values after pediatric liver transplantation: a consecutive cohort study

ObjectivesDoppler ultrasound (DUS) is the main imaging modality to evaluate vascular complications of pediatric liver transplants (LT). The current study aimed to determine reference values and their change over time.MethodsA consecutive cohort of pediatric patients undergoing an LT were retrospectively included between 2015 and 2020. Timepoints for standardized DUS were intra-operative and postoperative (day 0), days 1–7, months 1 and 3, and years 1 and 2. DUS measurements of the hepatic artery (HA), portal vein (PV), and hepatic vein(s) (HV) were included if there were no complications during 2 years follow-up. Measurements consisted of: peak systolic velocity (PSV) and resistive index (RI) for the HA, PSV for the PV, and venous pulsatility index (VPI) for the HV. Generalized estimating equations were used to analyze change over time.ResultsOne hundred twelve pediatric patients with 123 LTs were included (median age 3.3 years, interquartile range 0.7–10.1). Ninety-five HAs, 100 PVs, and 115 HVs without complications were included. Reference values for HA PSV and RI, PV PSV, and HV VPI were obtained for all timepoints (4043 included data points in total) and presented using 5th–95th percentiles and threshold values. All reference values changed significantly over time (p = 0.032 to p < 0.001).ConclusionsDUS reference values of hepatic vessels in children after LT are presented, reference values change over time with specific vessel-dependent patterns. Timepoint–specific reference values improve the interpretation of DUS values and may help to better weigh their clinical significance.Key Points• Doppler ultrasound reference values of pediatric liver transplantations are not static but change over time. Applying the correct reference values for the specific timepoint may further improve the interpretation of the measurements.• The pattern of change over time of Doppler ultrasound measurements differs between the hepatic vessel and measurement; knowledge of these patterns may help radiologists to better understand normal postoperative hemodynamic changes.

Implications of Pleural Fluid Composition in Persistent Pleural Effusion following Orthotopic Liver Transplant

Persistent pleural effusions (PPEf) represent a known complication of orthotopic liver transplant (OLT). However, their clinical relevance is not well described. We evaluated the clinical, biochemical, and cellular characteristics of post-OLT PPEf and assessed their relationship with longitudinal outcomes. We performed a retrospective cohort study of OLT recipients between 2006 and 2015. Included patients had post-OLT PPEf, defined by effusion persisting >30 days after OLT and available pleural fluid analysis. PPEf were classified as transudates or exudates (ExudLight) by Light's criteria. Exudates were subclassified as those with elevated lactate dehydrogenase (ExudLDH) or elevated protein (ExudProt). Cellular composition was classified as neutrophil- or lymphocyte-predominant. Of 1602 OLT patients, 124 (7.7%) had PPEf, of which 90.2% were ExudLight. Compared to all OLT recipients, PPEf patients had lower two-year survival (HR 1.63; p = 0.002). Among PPEf patients, one-year mortality was associated with pleural fluid RBC count (p = 0.03). While ExudLight and ExudProt showed no association with outcomes, ExudLDH were associated with increased ventilator dependence (p = 0.03) and postoperative length of stay (p = 0.03). Neutrophil-predominant effusions were associated with increased postoperative ventilator dependence (p = 0.03), vasopressor dependence (p = 0.02), and surgical pleural intervention (p = 0.02). In summary, post-OLT PPEf were associated with increased mortality. Ninety percent of these effusions were exudates by Light's criteria. Defining exudates using LDH only and incorporating cellular analysis, including neutrophils and RBCs, was useful in predicting morbidity.

Incidence, mortality, and risk factors associated with carbapenem-resistant Acinetobacter baumannii bacteremia within 30 days after liver transplantation.

Carbapenem-resistant Acinetobacter baumannii bacteremia (CRAB-B) is a fatal infectious complication of liver transplantation (LT). This study investigated the incidence, effects, and risk factors associated with CRAB-B during the early post-LT period. Among 1051 eligible LT recipients, 29 patients experienced CRAB-B within 30 days of LT with a cumulative incidence of 2.7%. In the patients with CRAB-B (n=29) and matched controls (n=145) by nested-case control design, the cumulative incidence of death on days 5, 10, and 30 from the index date was 58.6%, 65.5%, and 65.5%, and 2.1%, 2.8%, and 4.2%, respectively (p<.001). Pre-transplant MELD (OR 1.11, 95% confidence interval [CI] 1.04-1.19, p=.002), severe encephalopathy (OR 4.62, 95% CI 1.24-18.61, p=.025), donor body mass index (OR .57, 95% CI .41-.75, p<.001), and reoperation (OR 6.40, 95% CI 1.19-36.82, p=.032) were independent risk factors for 30-day CRAB-B. CRAB-B showed extremely high mortality within 30 days after LT, especially within 5 days after its occurrence. Therefore, assessment of risk factors and early detection of CRAB, followed by proper treatment, are necessary to control CRAB-B after LT.

A Narrative Review of the Evaluation and Management of Liver Transplant Complications in the Emergency Department

BackgroundLiver transplant recipients are prone to both short-term and long-term complications and may present to any emergency department. ObjectiveThis narrative review summarized key aspects of liver transplantation and reviewed the major complications that may result in emergency department presentation. DiscussionLiver transplantation is the only curative therapy for end-stage liver disease and the liver is the second most commonly transplanted solid organ. With nearly 100,000 living liver transplant recipients in the United States, these patients no longer present exclusively to transplantation centers. Critical complications may manifest with a variety of subtle signs and symptoms that must be considered by the emergency physician. Appropriate evaluation often includes laboratory analysis and imaging. Treatment may be time-sensitive and is variable depending on the specific complication. ConclusionsEmergency physicians in all settings must be prepared to evaluate and treat liver transplant recipients who present with potential graft- and life-threatening complications.

The Role of Microbiota in Liver Transplantation and Liver Transplantation-Related Biliary Complications

Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs.

Ultrasound-Targeted Microbubble Cavitation During Machine Perfusion Reduces Microvascular Thrombi and Graft Injury in a Rat Liver Model of Donation After Circulatory Death

Ischemic cholangiopathy is a process of bile duct injury that might result from peribiliary vascular plexus (PBP) thrombosis and remains a dreaded complication in liver transplantation from donors after circulatory death (DCD). The aim of this study was to propose a mechanical method of clot destruction to clear microvascular thrombi in DCD livers before transplantation. Sonothrombolysis (STL) is a process by which inertial cavitation of circulating microbubbles entering an ultrasound field create a high-energy shockwave at a microbubble-thrombus interface, causing mechanical clot destruction. The effectiveness of STL in DCD liver treatment remains unclear. We carried out STL treatment during normothermic, oxygenated, ex vivo machine perfusion (NMP), introducing microbubbles into the perfusate with the liver enveloped in an ultrasound field. The STL livers showed reduction in hepatic arterial and PBP thrombus and decreases in hepatic arterial and portal venous flow resistance, reduced parenchymal injury as measured by aspartate transaminase release and oxygen consumption, and improved cholangiocyte function. Light and electron microscopy showed reduction of hepatic arterial and PBP thrombus in STL livers compared with controls and preserved hepatocyte structure, sinusoid endothelial morphology, and biliary epithelial microvilli. In this model, STL improved flow and functional measures in DCD livers undergoing NMP. These data suggest a novel therapeutic approach to treat PBP injury in DCD livers, which may ultimately increase the pool of grafts available to patients awaiting liver transplantation.

CoQ10 alleviates hepatic ischemia reperfusion injury via inhibiting NLRP3 activity and promoting Tregs infiltration.

Hepatic ischemia-reperfusion injury (IRI) has been concerned as a main complication of liver surgery and transplantation. Previous studies show that reactive oxygen species (ROS) associated inflammation response and contribute to the liver damage during IRI. Coenzyme Q10 (CoQ10) has shown many beneficial effects on abrogating ROS production and ameliorating liver injury. This study found lower CoQ10 level in the process of liver IRI in a mouse model of hepatic IRI. Meanwhile, our results showed that CoQ10 administration significantly attenuate hepatic IRI proved by HE staining, serum ALT/AST. The NOD-like receptor protein 3 (NLRP3) inflammasome is activated by ROS which triggers the activation of inflammatory caspases. In this study, NLRP3 was significantly suppressed by CoQ10 while Foxp3 exhibited increased expression in liver. Furthermore, Kupffer cells (KCs) pretreated with CoQ10 under the condition of hypoxia and reoxygenation contributed to improved CD4+CD25+Foxp3+ regulatory T cells (Tregs) ratio in co-culture system. Furthermore, NLRP3 inflammasome activator treatment in vivo resulted in higher expression of caspase-1 and NLRP3 and reduction of Tregs in liver, which reversed the protection of CoQ10 in the liver injury. Taken together, our study discovered that CoQ10 can suppress NLRP3 activity in KCs and improves Foxp3+ Tregs differentiation depending on M2 macrophage polarization of KCs to ameliorate hepatic IRI.

CAR-OLT score predicts cardiac contraindications to liver transplant and 1-year cardiovascular complications after transplant

CAR-OLT score predicts cardiac contraindications to liver transplant and 1-year cardiovascular complications after transplant

Spatial transcriptomics analysis of zone-dependent hepatic ischemia-reperfusion injury murine model

Hepatic ischemia-reperfusion (I/R) injury is a common complication in liver transplantation. The connection between I/R-induced injury response and liver heterogeneity has yet to be fully understood. In this study, we converge histopathological examination with spatial transcriptomics to dissect I/R injury patterns and their associated molecular changes, which reveal that the pericentral zones are most sensitive to I/R injury in terms of histology, transcriptomic changes, and cell type dynamics. Bioinformatic analysis of I/R injury-related pathways predicts that celastrol can protect against liver I/R injury by inducing ischemic pre-conditioning, which is experimentally validated. Mechanistically, celastrol likely implements its protective effect against I/R injury by activating HIF1α signaling and represents a potential strategy for resolving liver I/R.

Long-Term Results of Endoscopic Metal Stenting for Biliary Anastomotic Stricture after Liver Transplantation.

(1) Background: Anastomotic biliary stricture (ABS) is a well-known complication of liver transplantation which can lead to secondary biliary cirrhosis and graft dysfunction. The goal of this study was to evaluate the long-term outcomes of endoscopic metal stenting of ABS in the setting of deceased donor liver transplantation (DDLT). (2) Methods: Consecutive DDLT patients with endoscopic metal stenting for ABS between 2010 and 2015 were screened. Data on diagnosis, treatment and follow-up (until June 2022) were collected. The primary outcome was endoscopic treatment failure defined as the need for surgical refection. (3) Results: Among the 465 patients who underwent LT, 41 developed ABS. It was diagnosed after a mean period of 7.4 months (+/-10.6) following LT. Endoscopic treatment was technically successful in 95.1% of cases. The mean duration of endoscopic treatment was 12.8 months (+/-9.1) and 53.7% of patients completed a 1-year treatment. After a mean follow-up of 6.9 years (+/-2.3), endoscopic treatment failed in nine patients (22%) who required surgical refection. Conclusions: Endoscopic management with metal stenting of ABS after DDLT was technically successful in most cases, and half of the patients had at least one year of indwelling stent. Endoscopic treatment long-term failure rate occurred in one fifth of the patients.

Efficacy and safety of adhesion barrier in living-donor liver transplantation with right liver graft to prevent delayed gastric emptying.

Delayed gastric emptying (DGE) is a common complication of liver transplantation. This study aimed to clarify the efficacy and safety of the application of an adhesion barrier for preventing DGE in living-donor liver transplantation. This retrospective study included 453 patients who underwent living-donor liver transplantation using a right lobe graft between January 2018 and August 2019, and the incidence of postoperative DGE and complications was compared between patients in whom adhesion barrier was used (n=179 patients) and those in whom adhesion barrier was not used (n=274 patients). We performed 1:1 propensity score matching between the 2 groups, and 179 patients were included in each group. DGE was defined according to the International Study Group for Pancreatic Surgery classification. The use of adhesion barrier was significantly associated with a lower overall incidence of postoperative DGE in liver transplantation (30.7 vs. 17.9%; p =0.002), including grades A (16.8 vs. 9.5%; p =0.03), B (7.3 vs. 3.4%; p =0.08), and C (6.6 vs. 5.5%; p =0.50). After propensity score matching, similar results were observed for the overall incidence of DGE (29.6 vs. 17.9%; p =0.009), including grades A (16.8 vs. 9.5%; p =0.04), B (6.7 vs. 3.4%; p =0.15), and C (6.1 vs. 5.0%; p =0.65). Univariate and multivariate analyses showed a significant correlation between the use of adhesion barrier and a low incidence of DGE. There were no statistically significant differences in postoperative complications between the 2 groups. The application of an adhesion barrier could be a safe and feasible method to reduce the incidence of postoperative DGE in living-donor liver transplantation.

Absorbable Biliary Stent as a Preventive Treatment of Biliary Complications in Liver Transplantation: A Pilot Study

Absorbable Biliary Stent as a Preventive Treatment of Biliary Complications in Liver Transplantation: A Pilot Study

Surgical site infections in liver transplantation in the era of multidrug-resistant bacteria.

Surgical site infection (SSI) is the major complication in orthotopic liver transplantation (LT). It is of prime importance to assess the incidence of infections in liver transplants and to analyze the risk factors associated with morbidity and mortality. Between 2014 and 2019, we performed a retrospective cohort study at the Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. The liver transplant procedure and its related infections were examined in 4 timepoints, both prior and post-surgery. Multiple random-intercept Poisson regression models with robust variance were fitted to calculate the adjusted risk ratios (RR) and the 95% confidence intervals (CI) according to selected recipient and donor variables. We included in the analysis 249 transplants (in 241 patients). The SSIs (mostly due to S. aureus, E. faecium, and K. pneumoniae) were 7 (2.8%) in the days following LT, increasing to 61 (24.5%) within the first month after LT, and declining to 35 (14.1%) between 31 and 60 days, and to 19 (7.6%) afterwards. The factors associated with increased risk of infection were age (RR=1.17 per 10 years, CI: 0.99-1.38), BMI (RR=1.04 per BMI Unit, CI: 0.99-1.08), donor age (RR=0.88 per 10 years, CI: 0.78-0.98), re-interventions (30 infections, RR=2.02, CI: 1.21-3.38) and the Roux-en-Y approach (25 infections, RR=2.75, CI: 1.47-5.15). The risk of infection occurred mainly in the first two months after LT. Important determinants were age and BMI, donor age, reinterventions, and Roux-en-Y procedure. Our study suggests that these factors should be assessed when performing LT.

EARLY PORTAL VEIN THROMBOSIS AFTER PEDIATRIC LIVER TRANSPLANTATION: ASSESMENT OF RISK FACTORS

Introduction: Despite advancements in surgical techniques, early portal vein thrombosis (ePVT) continues to be one of the major complications of liver transplantation (LT) in pediatric age group. Possible risk factors are portal vein diameter &lt; 5 mm, infancy, patient body weight &lt; 10 kg and high graft recipient weight ratios (GRWR &gt; 4.0). We retrospectively evaluated our records of pediatric LTs’ in terms of ePVT and possible risk factors determining development of this dreaded complication Study: Between January 2018 and January 2022, 228 LTs were performed for pediatric age (under the age of 18) group at Inonu University, Liver Transplantation Institute. Among these patients, 212 were eligible for the study. Patients with ePVT were defined as Portal Vein Thrombüs Group (PVTG) and patients with no Portal Vein thrombosis were defined in control group (CG). ePVT was described as detection of impeded portal venous outflow with imaging studies either perioperatively or within postoperative 3 days . Demographic, clinical and operative variables were retrospectively evaluated. Results: Among 212 LTs, 24 cases were complicated with ePVTs (11.3 %). Preoperative platelet counts, etiology of Budd-Chiari, postoperative hepatic artery thrombosis (HAT) and lower age were significantly higher for early PVT. In multivariate analysis, preoperative platelet levels, etiology of Budd-Chiari and postoperative HAT were significantly higher for PVT. One and 5 years overall survivals (OS) for PVTG and CG were 50.0 % - 50.0 % and 69 % - 63 % respectively. No significant OS difference was observed despite much more patients were died in PVTG. Conclusion: High preoperative platelet counts, Budd-Chiari syndrome and postoperative HAT are predictive factors for ePVT. Anti-thrombotic prophylaxies can be considered in high-risk patients. Venous jump grafts seem to have no effect on ePVT. Despite PVT increases the mortality rates, it cen be resolved easily with immediate reoperation.

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma.

Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma (HCC). The precise prediction of post-transplant lung metastasis in the early phase is of great value. The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways. We enrolled 241 HCC patients who underwent liver transplantation from three centers. Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1), and TNFR2, particularly for post-transplant lung metastasis. Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC. The expression of TNF was degraded in comparison to that in para-tumor tissues (P<0.001). The expression of key receptors in the TNF-dependent signaling pathway, TNFR1 and TNFR2, was higher in HCC tissues than in para-tumor tissues (P<0.001). TNF and TNFR1 showed no relationship with patients' outcomes, whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival (OS) and increased recurrence risk (5-year OS rate: 31.9% vs. 62.5%, P<0.001). Notably, elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis (hazard ratio: 1.146; P<0.001). Cox regression analysis revealed that TNFR2, Hangzhou criteria, age, and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis, and a novel nomogram was established accordingly. The nomogram achieved excellent prognostic efficiency (area under time-dependent receiver operating characteristic =0.755, concordance-index =0.779) and was superior to conventional models, such as the Milan criteria. TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC. A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

Assessment of the nutritional status of patients before, one, and three months after liver transplantation: A multi-center longitudinal study

Nutrition management is an important pre-operative and post-operative challenge in liver transplantation. Preoperative malnutrition is associated with increased length of intensive care unit (ICU) stay, mortality, and length of hospital stay in liver transplant patients. This study aimed to evaluate the nutritional status of patients before and after liver transplantation and post-transplant complications. This longitudinal study was conducted on liver transplant patients in Montaserieh Hospital, Mashhad and Firoozgar Hospital, Tehran from May 2021 to January 2022. Demographic characteristics, Subjective Global Assessment (SGA) standard questionnaire, anthropometric indices, laboratory analyses, and 3-day food records were collected before, one, and three months after transplantation. Thirty-nine patients with a mean age of 48.4±14.2 were evaluated. Prevalence of severe malnutrition was 43.6% (56.3% women and 34.8% men) before transplantation. Body mass index (BMI), body weight, lean mass, total body water, and total serum protein significantly decreased after transplantation compared to before transplantation (P<0.001). One month after transplantation, 54% of the patients lost more than 10% of their weight. Energy intake increased significantly after transplantation (P<0.001). A significant relationship was observed between BMI (P=0.005) and metabolic complications and between Arm Muscle Circumference and renal complications (P=0.003) after transplantation. A cut-off point of 4.6 was determined for the phase angle in terms of SGA three months after transplantation. Malnutrition, weight loss, and nutritional problems were common in liver transplantation patients. Screening for nutritional status is necessary in these patients to treat or prevent malnutrition-related complications.

Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis

Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A–GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A–GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A–GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.