With the concurrent development of traditional Chinese medicine （TCM） and metabolomics in the diagnosis and treatment of liver failure， techniques such as nuclear magnetic resonance， mass spectrometry， chromatography， metabolic flux analysis， and bioinformatics enable the qualitative or quantitative analysis of endogenous small molecule metabolites in animal models of liver failure and patients with liver failure. These methods help identify specific biomarkers for early diagnosis and clinical intervention. This article reviews recent advancements in metabolomics for the early diagnosis of liver failure， biomarker discovery， identification of TCM syndromes， and the application of TCM in treating liver failure， aiming to provide a basis for TCM-based diagnosis and treatment of liver failure.

Objective:To study the mechanistic role of Jiedu Huayu granule in improving intestinal mucosal barrier functional damage and protecting against liver failure in mice induced by D-galactosamine combined with lipopolysaccharide.Methods:Fifty mice were randomly divided into a normal group, a model group, a low-dose Jiedu Huayu granule group (4.16 g·kg -1·d -1), a medium-dose Jiedu Huayu granule group (8.32 g·kg -1·d -1), and a high-dose Jiedu Huayu granule group (16.64 g·kg -1·d -1). D-galactosamine combined with lipopolysaccharide was administered once to establish an acute liver failure mouse model, followed by corresponding drug intervention. Retro-orbital blood samples were collected to measure serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels six hours after modeling in mice. The endotoxin content was detected using the limulus reagent method. The content of serum interleukin-1β, tumor necrosis factor-α, and interferon-γ levels were detected using enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was used to observe liver and intestinal pathological tissues.Western blot and RT-PCR were used to determine the protein and mRNA expression of Occludin, Zo-1, Tricellulin, and CLDN3 in intestinal tissues. Multiple quantitative data were analyzed using one-way ANOVA, following a normal distribution. LSD-t test was used for statistical analysis between inter-groups. Results:The medium-and high-dose Jiedu Huayu granules had reduced and improved liver function impairment, liver pathological tissue damage, intestinal barrier damage, serum endotoxin and inflammatory factors ( P<0.05), and increased intestinal expression of occludin, Zo-1, Tricellulin, and CLDN3 ( P<0.05) in mice group with acute liver failure. Conclusion:Jiedu Huayu granules can reduce liver inflammatory damage, gut-derived endotoxemia, bacterial endotoxins entering the liver, and protect intestinal barrier function, thereby remissioning liver inflammation and antagonizing liver failure in mice with acute liver failure.

Cholesterol is an essential molecule for the biosynthesis of cell membranes and cell proliferation and differentiation,and the liver plays a central role in cholesterol metabolism and is responsible for the synthesis,uptake,secretion,and transport of cholesterol.The initial stages of cholesterol synthesis in the liver are particularly important,and abnormalities in such stages are closely associated with the progression of various liver diseases.Studies have shown that as a key rate-limiting enzyme in cholesterol biosynthesis,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGCR)has well-defined regulatory properties and has been confirmed as an important target for the regulation of various liver diseases.This article reviews the process of cholesterol metabolism,the degradation and regulatory mechanisms of HMGCR,and the application of inhibitors,as well as the role of HMGCR in liver diseases,in order to provide new insights for scientific research and the clinical prevention and treatment of liver diseases.

Cholesterol is an essential molecule for the biosynthesis of cell membranes and cell proliferation and differentiation， and the liver plays a central role in cholesterol metabolism and is responsible for the synthesis， uptake， secretion， and transport of cholesterol. The initial stages of cholesterol synthesis in the liver are particularly important， and abnormalities in such stages are closely associated with the progression of various liver diseases. Studies have shown that as a key rate-limiting enzyme in cholesterol biosynthesis， 3-hydroxy-3-methylglutaryl-coenzyme A reductase （HMGCR） has well-defined regulatory properties and has been confirmed as an important target for the regulation of various liver diseases. This article reviews the process of cholesterol metabolism， the degradation and regulatory mechanisms of HMGCR， and the application of inhibitors， as well as the role of HMGCR in liver diseases， in order to provide new insights for scientific research and the clinical prevention and treatment of liver diseases.

Objective Three different doses of diethylnitrosamine(DEN)were used to establish a rat primary liver cancer(PLC)model to establish an efficient,stable,and economical animal model of PLC.Methods Forty-five male SD rats were randomly divided into four groups:normal group,DEN 50 mg/kg dose group(low dose group),70 mg/kg dose group(medium dose group),and 200 mg/kg dose group(high dose group).There were 6 animals in the normal group and 13 animals in each of the other groups.The normal control group received no treatment.The model group and low dose groups were injected intraperitoneally twice a week during weeks 1～4 and once a week during weeks 5～12;the medium dose group was injected intraperitoneally once a week for 16 consecutive weeks;and the high dose group was administered only once in the first week.The rats in each group were then followed for 16 weeks.The establishment of the model and optimal evaluation were verified by survival rate,pathological tests,biochemical tests,liver and spleen index calculation,immunohistochemistry,enzyme-linked immunosorbent assay(ELISA),and other assays.Results The survival rate was 100％in the normal group,46.15％in the low dose group,69.23％in the medium dose group,and 84.61％in the high dose group.The liver tissues of the rats in the normal group showed no abnormality to the naked eye;the liver of the rats in the low dose group became darker in color,rougher in surface,with a small number of cancerous nodules and slightly hard texture;the liver of the rats in the medium dose group was rough in surface,with several small cancerous nodules and scattered massive occupying nodules and hard texture;The liver of rats in the high dose group became lighter in color,slightly rougher in surface,with no obvious cancerous nodules;HE staining showed that the liver tissues of rats in the low and medium dose groups were structurally disorganized,with large cellular heterogeneity and tumor cells.HE staining showed that the liver tissues of rats in the low and medium dose groups were structurally disorganized,with large cellular heterogeneity and tumor cell formation,while the structure of the liver lobules of the high dose group was unclear,with different degrees of edema,degeneration and necrosis of liver cells,and no obvious tumor cell formation was seen.Compared with the normal group,serum liver function alanine aminotransferase(ALT),aspartate aminotransferase(AST),and total bilirubin(TBIL)were elevated in the low,medium,and high dose groups;ALT and AST were significantly elevated in the low dose group(P<0.05),the difference was statistically significant,ALT,AST and TBIL were significantly elevated in the medium dose group(P<0.05),the difference was statistically significant,and the difference was statistically significant,although liver function in the high dose group was elevated,he increase was not significant,the difference was not statistically significant(P>0.05);compared with the normal group,the international normalized ratio(INR)of coagulation function was significantly higher in the low dose group,with a statistically significant difference(P<0.05),and the activated partial thromboplastin time(APTT),prothrombin time(PT),and alpha-fetoprotein(AFP)levels were increased(P<0.05),and the difference was not statistically significant;serum APTT,PT,INR,and AFP levels were significantly increased in the medium dose group(P<0.05),and the difference was statistically significant;serum PT and AFP levels were increased in the high dose group(P<0.05),the difference was statistically significant,and plasma APTT levels were slightly increased(P>0.05),the difference was not statistically significant;liver and spleen indexes were increased in the medium dose group(P<0.05),the spleen index increased in the low dose group(P<0.05),and the liver index increased in the high dose group(P<0.05),the difference was statistically significant;the optical density value of liver tissue AFP increased significantly in the low,medium and high dose groups(P<0.05),the difference was statistically significant.Conclusions Both the low and medium dose groups could successfully induce the PLC rat model,but the pathological changes and biochemical findings of the medium dose group were more consistent with the pathogenesis of human liver tissue from liver injury to hepatic fibrosis to cirrhosis to hepatocellular carcinoma,and the number of administrations of the drug is less,and the survival rate of the rats is higher so that a more cost-effective and superior PLC model can be established.

Objective To prepare a stable rat model of chronic liver failure to provide a tool for basic research.Methods Sixty-six SPF SD rats were divided into a normal group(n=18)and a modeling group(n=48).Rats in the modeling group received an intraperitoneal injection of 50％CCl4 olive oil solution(1.5 mL/kg,twice a week).Multidimensional assessment was performed at 8,16,and 24 weeks,respectively,including ultrasonic examination of liver morphology,hardness,portal vein diameter,and ascites,and collection of serum,plasma,and liver tissue to detect liver function,coagulation function,and blood ammonia levels.Liver tissue injury and fibrosis were observed by hematoxylin-eosin(HE)and Masson staining.Cognitive function was assessed using the water maze test.Survival were recorded simultaneously.Results Rats in the model group showed decreased activity and appetite,yellow urine,and increased abdominal circumference compared with the normal group.Ultrasound showed enhanced liver parenchyma echo in the model group that thickened with time,secondary ascites formation,portal vein dilation,and portal hypertension.Water maze and blood ammonia tests confirmed cognitive decline(memory and orientation loss)and hepatic encephalopathy in the model group.Gross observation showed that the liver in the model group was atrophied and appeared rough and uneven.HE staining showed hepatocyte swelling,steatosis,and necrosis,and Masson staining confirmed fibrosis progression with pseudolobule formation.The liver function indexes AST,ALT,TBIL and blood ammonia continued to increase,and coagulation dysfunction(prolonged PT and increased INR)gradually increased with the modeling process.Conclusions Intraperitoneal injection of 50％CCl4 olive oil solution(1.5 mL/kg,every week)for 24 weeks can stably simulate persistent chronic liver injury in rats and lead to the typical pathological changes and complications of chronic liver failure,based on the decompensation stage of cirrhosis.This model replicates the pathological evolution of human hepatitis from liver fibrosis → liver cirrhosis compensation → decompensation → chronic liver failure,providing a reliable modeling reference for the study of the mechanism of chronic liver failure.

Objective Three different doses of diethylnitrosamine(DEN)were used to establish a rat primary liver cancer(PLC)model to establish an efficient,stable,and economical animal model of PLC.Methods Forty-five male SD rats were randomly divided into four groups:normal group,DEN 50 mg/kg dose group(low dose group),70 mg/kg dose group(medium dose group),and 200 mg/kg dose group(high dose group).There were 6 animals in the normal group and 13 animals in each of the other groups.The normal control group received no treatment.The model group and low dose groups were injected intraperitoneally twice a week during weeks 1～4 and once a week during weeks 5～12;the medium dose group was injected intraperitoneally once a week for 16 consecutive weeks;and the high dose group was administered only once in the first week.The rats in each group were then followed for 16 weeks.The establishment of the model and optimal evaluation were verified by survival rate,pathological tests,biochemical tests,liver and spleen index calculation,immunohistochemistry,enzyme-linked immunosorbent assay(ELISA),and other assays.Results The survival rate was 100％in the normal group,46.15％in the low dose group,69.23％in the medium dose group,and 84.61％in the high dose group.The liver tissues of the rats in the normal group showed no abnormality to the naked eye;the liver of the rats in the low dose group became darker in color,rougher in surface,with a small number of cancerous nodules and slightly hard texture;the liver of the rats in the medium dose group was rough in surface,with several small cancerous nodules and scattered massive occupying nodules and hard texture;The liver of rats in the high dose group became lighter in color,slightly rougher in surface,with no obvious cancerous nodules;HE staining showed that the liver tissues of rats in the low and medium dose groups were structurally disorganized,with large cellular heterogeneity and tumor cells.HE staining showed that the liver tissues of rats in the low and medium dose groups were structurally disorganized,with large cellular heterogeneity and tumor cell formation,while the structure of the liver lobules of the high dose group was unclear,with different degrees of edema,degeneration and necrosis of liver cells,and no obvious tumor cell formation was seen.Compared with the normal group,serum liver function alanine aminotransferase(ALT),aspartate aminotransferase(AST),and total bilirubin(TBIL)were elevated in the low,medium,and high dose groups;ALT and AST were significantly elevated in the low dose group(P<0.05),the difference was statistically significant,ALT,AST and TBIL were significantly elevated in the medium dose group(P<0.05),the difference was statistically significant,and the difference was statistically significant,although liver function in the high dose group was elevated,he increase was not significant,the difference was not statistically significant(P>0.05);compared with the normal group,the international normalized ratio(INR)of coagulation function was significantly higher in the low dose group,with a statistically significant difference(P<0.05),and the activated partial thromboplastin time(APTT),prothrombin time(PT),and alpha-fetoprotein(AFP)levels were increased(P<0.05),and the difference was not statistically significant;serum APTT,PT,INR,and AFP levels were significantly increased in the medium dose group(P<0.05),and the difference was statistically significant;serum PT and AFP levels were increased in the high dose group(P<0.05),the difference was statistically significant,and plasma APTT levels were slightly increased(P>0.05),the difference was not statistically significant;liver and spleen indexes were increased in the medium dose group(P<0.05),the spleen index increased in the low dose group(P<0.05),and the liver index increased in the high dose group(P<0.05),the difference was statistically significant;the optical density value of liver tissue AFP increased significantly in the low,medium and high dose groups(P<0.05),the difference was statistically significant.Conclusions Both the low and medium dose groups could successfully induce the PLC rat model,but the pathological changes and biochemical findings of the medium dose group were more consistent with the pathogenesis of human liver tissue from liver injury to hepatic fibrosis to cirrhosis to hepatocellular carcinoma,and the number of administrations of the drug is less,and the survival rate of the rats is higher so that a more cost-effective and superior PLC model can be established.

Objective To prepare a stable rat model of chronic liver failure to provide a tool for basic research.Methods Sixty-six SPF SD rats were divided into a normal group(n=18)and a modeling group(n=48).Rats in the modeling group received an intraperitoneal injection of 50％CCl4 olive oil solution(1.5 mL/kg,twice a week).Multidimensional assessment was performed at 8,16,and 24 weeks,respectively,including ultrasonic examination of liver morphology,hardness,portal vein diameter,and ascites,and collection of serum,plasma,and liver tissue to detect liver function,coagulation function,and blood ammonia levels.Liver tissue injury and fibrosis were observed by hematoxylin-eosin(HE)and Masson staining.Cognitive function was assessed using the water maze test.Survival were recorded simultaneously.Results Rats in the model group showed decreased activity and appetite,yellow urine,and increased abdominal circumference compared with the normal group.Ultrasound showed enhanced liver parenchyma echo in the model group that thickened with time,secondary ascites formation,portal vein dilation,and portal hypertension.Water maze and blood ammonia tests confirmed cognitive decline(memory and orientation loss)and hepatic encephalopathy in the model group.Gross observation showed that the liver in the model group was atrophied and appeared rough and uneven.HE staining showed hepatocyte swelling,steatosis,and necrosis,and Masson staining confirmed fibrosis progression with pseudolobule formation.The liver function indexes AST,ALT,TBIL and blood ammonia continued to increase,and coagulation dysfunction(prolonged PT and increased INR)gradually increased with the modeling process.Conclusions Intraperitoneal injection of 50％CCl4 olive oil solution(1.5 mL/kg,every week)for 24 weeks can stably simulate persistent chronic liver injury in rats and lead to the typical pathological changes and complications of chronic liver failure,based on the decompensation stage of cirrhosis.This model replicates the pathological evolution of human hepatitis from liver fibrosis → liver cirrhosis compensation → decompensation → chronic liver failure,providing a reliable modeling reference for the study of the mechanism of chronic liver failure.

Objective:To study the mechanistic role of Jiedu Huayu granule in improving intestinal mucosal barrier functional damage and protecting against liver failure in mice induced by D-galactosamine combined with lipopolysaccharide.Methods:Fifty mice were randomly divided into a normal group, a model group, a low-dose Jiedu Huayu granule group (4.16 g·kg -1·d -1), a medium-dose Jiedu Huayu granule group (8.32 g·kg -1·d -1), and a high-dose Jiedu Huayu granule group (16.64 g·kg -1·d -1). D-galactosamine combined with lipopolysaccharide was administered once to establish an acute liver failure mouse model, followed by corresponding drug intervention. Retro-orbital blood samples were collected to measure serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels six hours after modeling in mice. The endotoxin content was detected using the limulus reagent method. The content of serum interleukin-1β, tumor necrosis factor-α, and interferon-γ levels were detected using enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was used to observe liver and intestinal pathological tissues.Western blot and RT-PCR were used to determine the protein and mRNA expression of Occludin, Zo-1, Tricellulin, and CLDN3 in intestinal tissues. Multiple quantitative data were analyzed using one-way ANOVA, following a normal distribution. LSD-t test was used for statistical analysis between inter-groups. Results:The medium-and high-dose Jiedu Huayu granules had reduced and improved liver function impairment, liver pathological tissue damage, intestinal barrier damage, serum endotoxin and inflammatory factors ( P<0.05), and increased intestinal expression of occludin, Zo-1, Tricellulin, and CLDN3 ( P<0.05) in mice group with acute liver failure. Conclusion:Jiedu Huayu granules can reduce liver inflammatory damage, gut-derived endotoxemia, bacterial endotoxins entering the liver, and protect intestinal barrier function, thereby remissioning liver inflammation and antagonizing liver failure in mice with acute liver failure.

Acute liver failure(ALF)is one of the most critical liver diseases in clinical practice and seriously affects the life and health of Chinese people.Due to its high morbidity and mortality rates,unclear pathogenesis,and limited treatment methods,ALF has become a major problem that needs to be solved urgently in the field of liver diseases.In recent years,more and more studies have shown that endoplasmic reticulum stress is a key biological process in the progression of ALF,and the IRE1α/TRAF2/JNK pathway,as a part of endoplasmic reticulum stress signaling,plays a role in amplifying inflammatory response,promoting hepatocyte apoptosis,and inhibiting liver regeneration ability during the progression of diseases.As a traditional treasure of China,traditional Chinese medicine has become a research hotspot in search for effective prevention and treatment drugs for ALF from monomers of Chinese herbs.This article elaborates on the mechanism of action of the IRE1α/TRAF2/JNK pathway in the progression of ALF and summarizes the potential value of several monomers of Chinese herbs in regulating this pathway,such as salidroside,Fructus Broussonetiae,Fructus Psoraleae+Schisandra chinensis,baicalein,genipin,kaempferol,resveratrol,sea buckthorn polysaccharide extract,and luteol,in order to provide a reference for further research and clinical practice of ALF.