Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Yamada, Naoya; Karasawa, Tadayoshi; Wakiya, Taiichi; Sadatomo, Ai; Ito, Homare; Kamata, Ryo; Watanabe, Sachiko; Komada, Takanori; Kimura, Hiroaki; Sanada, Yukihiro; Sakuma, Yoshiki; Mizuta, Koichi; Ohno, Nobuhiko; Sata, Naohiro; Takahashi, Masafumi

doi:10.1111/ajt.15773

Cited by 193 publications

(154 citation statements)

References 39 publications

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“…5,17,18 Emerging evidence suggested that ferroptosis occurs in multiple organs under ischemia conditions, such as heart IR 19 or even liver transplantation in the clinical setting. 20 Moreover, ferroptosis have been implicated in intestinal IR-induced lung injury caused by the release of bacteria-derived endotoxins and pro-inflammatory cytokines from remote injured tissue. 21,22 Thus, an improved understanding of the mechanisms underlying ferroptosis after IR is critical for identifying potential therapies to prevent and mitigate LIRI-induced graft damage.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia‐reperfusion

Cheng

et al. 2020

FASEB j.

115

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Lung ischemia-reperfusion (IR) injury is a common clinical pathology associated with high mortality. Ferroptosis, a novel mode of cell death elicited by iron-dependent phospholipid peroxidation, has been implicated in ischemic events. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is one of the main enzymes in pro-ferroptotic lipid metabolism. In this study, the involvement of ferroptotic death in different durations of reperfusion was evaluated by assessing the iron content, malondialdehyde, and glutathione levels, ferroptosis-related protein expression, and mitochondria morphology. The roles of ferroptosis-specific inhibitor, liproxastin-1 (Lip-1), and ACSL4 modulation in a preventive regimen were assessed in vivo and in vitro. The hallmarks of pulmonary function, such as histological lung injury score, wet/dry ratio, and oxygenation index, were evaluated as well. Results showed that lung IR increased the tissue iron content and lipid peroxidation accumulation, along with key protein (GPX4 and ACSL4) expression alteration during reperfusion. Pretreatment with Lip-1 inhibited ferroptosis and ameliorated lung IR-induced injury in animal and cell models. In addition, administering ACSL4 inhibitor rosiglitazone before ischemia diminished the ferroptotic damage in IR-injured lung tissue, consistent with the protective effect of ACSL4 knockdown on lung epithelial cells subjected to hypoxia/reoxygenation. Thus, this study delineated that IR-induced ferroptotic cell death in lung tissue and ACSL4 were correlated with this process. Inhibition of ferroptosis and ACSL4 mitigated the ferroptotic damage in IR-induced lung injury by reducing lipid peroxidation and increasing the glutathione and GPX4 levels.

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Section: Introductionmentioning

confidence: 99%

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia‐reperfusion

Cheng

et al. 2020

FASEB j.

115

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“…In a murine model of hepatic I/R injury, lipid peroxidation and ferroptosis marker PTGS2 were elicited, all of which were markedly prevented by Fer-1 or αtocopherol. The mice fed with high iron diet represented deleterious I/R injury due to overload, and these manifestation was attenuated by DFO 104 . Furthermore, Li et al found that ferroptosis inhibition by Lip-1 significantly decreased myeloperoxidase (MPO) activity and mitigated histological injury in liver 100 .…”

Section: Other Liver Diseasesmentioning

confidence: 99%

“…Moreover, hepatic I/R injury induces inflammatory cascade and immunological reactions, which dampens normal graft liver function and leads to poor prognosis of the recipients 103 . Iron load of the donor has been proved to be an independent risk factor for hepatic I/R injury in pediatric living donor LTx 104 . In a murine model of hepatic I/R injury, lipid peroxidation and ferroptosis marker PTGS2 were elicited, all of which were markedly prevented by Fer-1 or αtocopherol.…”

Section: Other Liver Diseasesmentioning

confidence: 99%

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

et al. 2020

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Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

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“…Furthermore, investigation of IR injury in combination with a macrovesicular steatotic model also becomes essential, as studies have shown that such livers are more susceptible to IR injury compared with microvesicular steatosis. Interestingly, ferroptosis, an iron-dependent non-apoptotic cell death pathway, has been linked to hepatic IR injury [ 145 ]. A recent study in a murine model of hepatic IR injury has shown the upregulation of the ferroptosis marker prostaglandin-endoperoxide synthase 2 ( Ptgs2) after IR insult which was prevented by the ferroptosis inhibitor, ferrostatin-1 (Fer-1) or α-tocopherol [ 145 ].…”

Section: Necroptosis In Steatotic Hepatic Injury and Steatotic Irmentioning

confidence: 99%

“…Interestingly, ferroptosis, an iron-dependent non-apoptotic cell death pathway, has been linked to hepatic IR injury [ 145 ]. A recent study in a murine model of hepatic IR injury has shown the upregulation of the ferroptosis marker prostaglandin-endoperoxide synthase 2 ( Ptgs2) after IR insult which was prevented by the ferroptosis inhibitor, ferrostatin-1 (Fer-1) or α-tocopherol [ 145 ]. More studies are indeed required to investigate the involvement of ferroptosis during steatotic liver undergoing IR injury.…”

Section: Necroptosis In Steatotic Hepatic Injury and Steatotic Irmentioning

confidence: 99%

Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury

Baidya

Crawford

Gautheron

et al. 2020

IJMS

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While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.

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Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Cited by 193 publications

References 39 publications

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia‐reperfusion

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia‐reperfusion

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury

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