Liver transplantation is the ultimate method for treating end-stage liver disease. With the increasing prevalence of obesity, the number of patients with non-alcoholic fatty liver, a common cause of chronic liver disease, is on the rise and may become the main cause of liver transplantation in the future. With the increasing gap between the number of donor livers and patients waiting for liver transplantation and the increasing prevalence of non-alcoholic fatty liver, the proportion of steatosis livers among non-standard donor organs is also increasing. Ischemia-reperfusion injury has historically been the focus of attention in the liver transplantation process, and severe ischemia-reperfusion injury leads to adverse outcomes of liver transplantation. Studies have shown that the production of reactive oxygen species and subsequent oxidative stress play a key role in the pathogenesis of hepatic ischemia and reperfusion injury and non-alcoholic fatty liver. Furthermore, the sensitivity of fatty liver transplantation to ischemia-reperfusion injury has been suggested to be related to the production of reactive oxygen species (ROS) and oxidative stress. In ischemia-reperfusion injury, Kupffer cell and macrophage activation along with mitochondrial damage and the xanthine/xanthine oxidase system promote marked reactive oxygen species production and the inflammatory response and apoptosis, resulting in liver tissue injury. The increased levels of ROS and lipid peroxidation products, vicious circle of ROS and oxidative stress along with mitochondrial dysfunction promoted the progress of non-alcoholic fatty liver. In contrast to the non-fatty liver, a non-alcoholic fatty liver produces more reactive oxygen species and suffers more serious oxidative stress when subjected to ischemia-reperfusion injury. We herein review the effects of reactive oxygen species on ischemia-reperfusion injury and non-alcoholic fatty liver injury as well as highlight several treatment approaches.

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Reactive Oxygen Species Induce Fatty Liver and Ischemia-Reperfusion Injury by Promoting Inflammation and Cell Death

Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported.Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC.Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells.In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC. 

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System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Hepatic ischemia-reperfusion injury is a major cause of post-operative hepatic dysfunction and liver failure after transplantation. Mitochondrial pathways can be either beneficial or detrimental to hepatic cell apoptosis during hepatic ischemia/reperfusion injury, depending on multiple factors. Hepatic ischemia/reperfusion injury may be induced by opened mitochondrial permeability transition pore, released apoptosis-related proteins, up-regulated B-cell lymphoma-2 gene family proteins, unbalanced mitochondrial dynamics, and endoplasmic reticulum stress, which are integral parts of mitochondrial pathways. In this review, we discuss the role of mitochondrial pathways in apoptosis that account for the most deleterious effect of hepatic ischemia/reperfusion injury.

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Role of Mitochondrial Pathways in Cell Apoptosis during He-Patic Ischemia/Reperfusion Injury

Pterostilbene alleviates liver ischemia/reperfusion injury via PINK1-mediated mitophagy

Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome.

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MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury

Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.

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The Role of Mitochondria in Liver Ischemia-Reperfusion Injury: From Aspects of Mitochondrial Oxidative Stress, Mitochondrial Fission, Mitochondrial Membrane Permeable Transport Pore Formation, Mitophagy, and Mitochondria-Related Protective Measures.

The mechanisms of renin–angiotensin system in hepatocellular carcinoma: From the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures

Xuan Wang

Papers

The Role of Mitochondria in Liver Ischemia-Reperfusion Injury: From Aspects of Mitochondrial Oxidative Stress, Mitochondrial Fission, Mitochondrial Membrane Permeable Transport Pore Formation, Mitophagy, and Mitochondria-Related Protective Measures.

The mechanisms of renin–angiotensin system in hepatocellular carcinoma: From the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures