• biomarkers
• liver diseases
• macrophage
• programmed cell death
• targeted therapy

• Humans
• Liver Diseases/metabolism
• Liver Diseases/drug therapy
• Liver Diseases/immunology
• Liver Diseases/therapy
• Macrophages/metabolism
• Macrophages/immunology
• Biomarkers/metabolism
• Animals
• Apoptosis/drug effects
• Molecular Targeted Therapy

• 82360132 National Natural Science Foundation of China
• ldyyyn2018-62 , ldyyyn2020-02 , ldyyyn2020-14 The Fund of the First Hospital of Lanzhou University
• 21JR7RA392 Gansu Clinical Medical Research Center of Infection & Liver Diseases
• 2023-2-76 Lanzhou Science and Technology Planning Project
• RGGJJ-2021-004 Special Fund for Artificial Liver
• 2022B-007 Education technology innovation project of Gansu Province

• Hemochromatosis
• Hemojuvelin
• Hepcidin
• Iron metabolism
• Liver fibrosis

• Animals
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Genetic Background
• Male

• Animals
• Iron/metabolism
• Iron-Regulatory Proteins/genetics
• Iron-Regulatory Proteins/metabolism
• Transcription Factors/metabolism
• Homeostasis/physiology
• Oxidative Stress
• Mammals/metabolism

• Animals
• Humans
• Mice
• Anemia/metabolism
• Erythropoiesis/genetics
• Hemochromatosis/genetics
• Hemochromatosis/metabolism
• Iron Overload/genetics
• Iron Overload/metabolism
• Mice, Knockout
• Myelodysplastic Syndromes/genetics
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism

• MC_UU_00008/10 Medical Research Council
• MC_UU_00036/4 Medical Research Council

• Humans
• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/therapy
• Iron Overload/diagnosis
• Iron Overload/etiology
• Iron Overload/therapy
• Liver Cirrhosis/complications
• Phlebotomy/adverse effects
• Genetic Testing

• COVID-19
• Cytokine storm
• Direct hepatocyte injury
• Endotheliopathy
• Immuno-thromboinflammation
• Liver injury
• SARS-CoV-2

• Humans
• COVID-19/complications
• SARS-CoV-2
• RNA, Viral
• Endothelial Cells
• Incidence
• Chemical and Drug Induced Liver Injury, Chronic/complications
• Population Groups
• Liver Diseases
• Risk Factors
• Prognosis

• 4-hydroxynonenal (HNE)
• Hfe−/− mouse
• erythrocyte membrane proteins
• hemochromatosis
• lipid peroxidation
• oxidative stress
• protein modification

Oxidative damage can lead to severe ovarian dysfunctions and even premature ovarian failure. Nrf2, a significant transcription factor that regulates the oxidative stress response of cells, declines with age. Daphnetin, as a kind of natural Chinese herbal medicine, can activate Nrf2 and further promote the antioxidant defense of cells. However, whether Daphnetin treatment can protect ovary from premature ovarian failure and the specific mechanism involved are not understood. This study aimed to investigate the protective function of Daphnetin against the ovarian aging induced by D-galactose in wild-type and Nrf2^−/− mice. Female C57BL/6 mice with Wild-type and Nrf2^−/− were divided into five groups separately and the premature ovarian failure model were established by D-galactose and then Daphnetin and VE were given for treatment. After 42 days, ovaries tissue and serum were collected for biochemical determination, H&E staining, Immunohistochemical staining and western blot analysis. In the WT-POF group, ovarian function was broke, and the expression of the ovarian senescence-associated protein P16 and the level of oxidative stress were significantly increased, while the expression of the anti-senescence protein klotho was significantly decreased. In addition, the expression of Nrf2 and the antioxidases GCLC, HO-1 and NQO1 were decreased, but TXNIP and NLRP3 were significantly increased. Furthermore, the characteristics of premature ovarian failure were more significant in Nrf2 knockout mice than in wild-type mice, especially the expression of NLRP3 and TXNIP. Moreover, daphnetin, an Nrf2 activator, rescued d-gal-induced POF in a dose-dependent manner, while the protective effect was weakened or even lost in Nrf2 knockout mice. Our results suggested that daphnetin is likely to be a candidate drug for premature ovarian failure treatment and it is mostly possible referred to the molecular mechanism of increasing Nrf2 expression and inhibiting NLRP3 activation in the ovarian aging process.

• National Key Research and Development Program of China
• National Natural Science Foundation of China
• Natural Science Foundation of Jilin Province

• LSEC
• iron
• liver fibrosis
• sinusoidal endothelial cells

• BMP
• HIF
• PHD
• antioxidant
• hepcidin
• oxygen

• Homeostasis
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Iron/metabolism
• Kelch-Like ECH-Associated Protein 1/metabolism
• NF-E2-Related Factor 2/metabolism
• Oxidation-Reduction

• MC_UU_00008/10 Medical Research Council
• MC_UU_12010/10 Medical Research Council

• erythropoiesis
• hematopoiesis
• iron
• oxidative stress

• Activin Receptors, Type II/pharmacology
• Erythropoiesis/drug effects
• Humans
• Immunoglobulin Fc Fragments/pharmacology
• Iron/metabolism
• Myelodysplastic Syndromes/drug therapy
• Myelodysplastic Syndromes/metabolism
• Peptide Hormones/metabolism
• Recombinant Fusion Proteins/pharmacology
• beta-Thalassemia/drug therapy
• beta-Thalassemia/metabolism

• R01 DK090554 NIDDK NIH HHS
• R01 DK095112 NIDDK NIH HHS

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies.

• COVID-19-related liver injury
• Nuclear factor erythroid 2-related factor 2
• Inflammatory mediator
• Oxidative stress
• Therapeutic targets

• COVID-19/pathology
• Humans
• Inflammation Mediators/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Diseases/virology
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress
• SARS-CoV-2
• Signal Transduction

• Aging
• Geriatrics
• Nuclear factor erythroid 2 like
• Pharmacogenomics
• Precision medicine

• Nrf2
• PGC-1α
• aspartame
• gluconeogenesis
• hypoglycemia
• inflammasome
• lipid
• lipid peroxidation
• liver fibrosis

• Aging
• Bach1
• HNE
• Lipid peroxidation
• Nrf2
• Oxidative stress

Hepatic iron overload is well known as an important risk factor for progression of liver diseases; however, it is unknown whether it can alter the susceptibility to drug-induced hepatotoxicity. Here we investigate the pathological roles of iron overload in two single-dose models of chemically-induced liver injury. Rats were fed a high-iron (Fe) or standard diet (Cont) for four weeks and were then administered with allyl alcohol (AA) or carbon tetrachloride (CCl₄). Twenty-four hours after administration mild mononuclear cell infiltration was seen in the periportal/portal area (Zone 1) in Cont-AA group, whereas extensive hepatocellular necrosis was seen in Fe-AA group. Centrilobular (Zone 3) hepatocellular necrosis was prominent in Cont-CCl₄ group, which was attenuated in Fe-CCl₄ group. Hepatic lipid peroxidation and hepatocellular DNA damage increased in Fe-AA group compared with Cont-AA group. Hepatic caspase-3 cleavage increased in Cont-CCl₄ group, which was suppressed in Fe-CCl₄ group. Our results showed that dietary iron overload exacerbates AA-induced Zone-1 liver injury via enhanced oxidative stress while it attenuates CCl₄-induced Zone-3 liver injury, partly via the suppression of apoptosis pathway. This study suggested that susceptibility to drugs or chemical compounds can be differentially altered in iron-overloaded livers.

• acute liver injury
• apoptosis
• ferroptosis
• hepatic iron overload

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia–reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

• cell death
• ferroptosis
• iron metabolism
• liver

• Inflammatory response
• Liver fibrosis
• MCP-1
• Nrf2
• Oxidative damage

• Animals
• Carbon Tetrachloride/toxicity
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/pathology
• Hepatocytes/pathology
• Liver/pathology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Mice
• NF-E2-Related Factor 2/genetics

• HO-1
• Heme oxygenase-1
• Liraglutide
• Methotrexate
• Nrf 2
• Nuclear factor erythroid 2-related factor2
• P-CREB
• Phosphorylated cAMP response element-binding protein

• Animals
• Chemical and Drug Induced Liver Injury
• Cyclic AMP Response Element-Binding Protein/metabolism
• Dose-Response Relationship, Drug
• Heme Oxygenase-1/metabolism
• Hep G2 Cells
• Humans
• Liraglutide/pharmacology
• Liver/drug effects
• Male
• Methotrexate/toxicity
• NF-E2-Related Factor 2/metabolism
• Rats
• Rats, Sprague-Dawley
• Signal Transduction

• Nrf2
• copper
• homeostasis
• iron
• selenium
• zinc

• Animals
• Copper/blood
• Copper/metabolism
• Duodenum/metabolism
• Female
• Homeostasis
• Iron/blood
• Iron/metabolism
• Liver/metabolism
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2/blood
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Selenium/blood
• Selenium/metabolism
• Zinc/blood
• Zinc/metabolism

• FOR 2558 Deutsche Forschungsgemeinschaft

• Bone Morphogenetic Protein 6/physiology
• Hepcidins/physiology
• Homeostasis/physiology
• Humans
• Iron/metabolism
• NF-E2-Related Factor 2/physiology
• beta-Thalassemia/physiopathology

• MOP-14100 CIHR
• MC_UU_00008/10 Medical Research Council
• MC_UU_00016/14 Medical Research Council
• MC_UU_12010/10 Medical Research Council
• Wellcome Trust
• MC_PC_14131 Medical Research Council
• 110159/Z/15/Z Wellcome Trust
• 109965/Z/15/Z Wellcome Trust
• MC_UU_12009/15 Medical Research Council
• MC_U105663142 Medical Research Council
• R01 DK087727 NIDDK NIH HHS
• MOP-126064 CIHR

Iron is implicated in the pathogenesis of a number of human liver diseases. Hereditary hemochromatosis is the classical example of a liver disease caused by iron, but iron is commonly believed to contribute to the progression of other forms of chronic liver disease such as hepatitis C infection and nonalcoholic fatty liver disease. In this review, we present data from cell culture experiments, animal models, and clinical studies that address the hepatotoxicity of iron. These data demonstrate that iron overload is only weakly fibrogenic in animal models and rarely causes serious liver damage in humans, calling into question the concept that iron overload is an important cause of hepatotoxicity. In situations where iron is pathogenic, iron-induced liver damage may be potentiated by coexisting inflammation, with the resulting hepatocyte necrosis an important factor driving the fibrogenic response. Based on the foregoing evidence that iron is less hepatotoxic than is generally assumed, claims that assign a causal role to iron in liver injury in either animal models or human liver disease should be carefully evaluated.

• chelation
• cirrhosis
• hemochromatosis
• iron
• liver injury
• phlebotomy

• Activation, Metabolic
• Animals
• Drug Therapy
• Humans
• Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors
• Kelch-Like ECH-Associated Protein 1/drug effects
• Kelch-Like ECH-Associated Protein 1/genetics
• NF-E2-Related Factor 2/drug effects
• NF-E2-Related Factor 2/genetics

• 10268 Cancer Research UK
• 18644 Cancer Research UK
• MR/N009851/1 Medical Research Council
• BB/L01923X/1 Biotechnology and Biological Sciences Research Council

• Autophagy
• Cartilage endplate
• Intervertebral disk degeneration
• Nrf2/Keap1
• TNF-α

• Aging
• Epigenetic modifications
• Negative regulation
• Nrf2

Apoptosis and oxidative stress are essential for the pathogenesis of acute liver failure and fulminant hepatic failure. Human placental hydrolysate (hPH) has been reported to possess antioxidant and anti-inflammatory properties. In the present study, the protective effects of hPH against D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced hepatocyte apoptosis were investigated in vivo. In addition, the molecular mechanisms underlying the anti-apoptotic activities of hPH against D-GalN-induced cell death in vitro were examined. Male Sprague-Dawley rats were injected with D-GaIN/LPS with or without the administration of hPH. Rats were sacrificed 24 h after D-GaIN/LPS intraperitoneal injection, and the blood and liver samples were collected for future inflammation and hepatotoxicity analyses. Changes in cell viability, apoptosis protein expression, mitochondrial mass, mitochondrial membrane potential, reactive oxygen species generation, and the levels of proteins and mRNA associated with a protective mechanism were determined in HepG2 cells pretreated with hPH for 2 h prior to D-GalN exposure. The findings suggested that hPH treatment effectively protected against D-GalN/LPS-induced hepatocyte apoptosis by reducing the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, interleukin-6, and tumor necrosis factor-α, and increasing the level of proliferating cell nuclear antigen. It was also found that hPH inhibited the apoptotic cell death induced by D-GalN. hPH activated the expression of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and catalase, which were further upregulated by the Kelch-like ECH2-associated protein 1-p62-nuclear factor-erythroid 2-related factor 2 pathway, a component of oxidative stress defense mechanisms. Furthermore, hPH markedly reduced cytosolic and mitochondrial reactive oxygen species and rescued mitochondrial loss and dysfunction through the reduction of damage-regulated autophagy modulator, p53, and C/EBP homologous protein. Collectively, hPH exhibited a protective role in hepatocyte apoptosis by inhibiting oxidative stress and maintaining cell homeostasis. The underlying mechanisms may be associated with the inhibition of endoplasmic reticulum stress and minimization of the autophagy progress.