OBJECTIVE To explore the anti-liver fibrosis effect and mechanism of Atractylenolide Ⅲ-induced hepatic stellate cell(HSC)senescence.METHODS ASCT2 siRNA and Atractylenolide Ⅲ(40 μmol·L-1)acted on human hepatic stellate cells LX2 respectively to inhibit ASCT2,MTT was used to evaluate cell viability,EdU method was used to detect cell proliferation,and se-nescence associated-β-galactosidase(SA-β-Gal)staining was used to detect cell senescence;Western blot was used to detect chan-ges in the LC3-Ⅱ/Ⅰ ratio in LX2 cells,laser confocal detection was used to detect changes in LC3 autophagy flow and error protein accumulation,and the fluorescence of the lysosomal marker LAMP1 was also observed to detect lysosomal function and quantity;kits were applied to detect ROS and MDA levels as well as SOD activity in LX2 cells,and flow cytometry was used to analyze mitochondrial ROS levels and membrane potential.A CCl4-induced mouse liver fibrosis model was constructed.Atractylenolide Ⅲ was administered at 20,30,or 40 mg·kg-1.HE,Masson,and Sirius Red staining were used to observe liver tissue damage and collagen deposition.Western blot was used to detect the expression levels of P21 and P16 in mice in each group,and SA-β-Gal staining and immunohistochemistry were used to analyze the situation and origin of senescent cells.RESULTS After inhibiting ASCT2,the viabil-ity of LX2 cells decreased and senescence increased(P<0.01).Meanwhile,the autophagy function was enhanced and the number of lysosomes was increased but the function was weakened.After adding chloroquine(CQ)to clear lysosomes,the cell viability and auto-phagy function increased(P<0.01).After inhibiting ASCT2,the levels of MDA and ROS in LX2 cells increased,and the activity of SOD decreased(P<0.01).Among them,the level of mitochondrial ROS increased and the membrane potential decreased(P<0.01).After adding rotenone,the cellular redox homeostasis was improved,and the number of lysosomes was restored(P<0.01).In vivo experimental results showed that compared with the model group,Atractylenolide Ⅲ improved liver tissue structural damage and collagen deposition,induced HSC senescence in liver tissue of mice with liver fibrosis,and inhibited HSC activation marker α-smooth muscle actin(α-SMA),promoted the expression of senescence indicators P16 and P21(P<0.01).CONCLUSION Atractylenol-ide Ⅲ induces an increase in mitochondrial ROS and a decrease in membrane potential by inhibiting ASCT2,which further promotes the enhancement of HSC autophagy function,increases the number of lysosomes and weakens their function,thereby inducing the se-nescence of activated HSCs.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Liver sinusoidal endothelial cells (LSECs) are the highest proportion of liver non-parenchymal cells with fenestrae structure and high endocytic ability maintaining liver homeostasis and playing an indispensable role in the physiology and patholo-gy of the liver.LSECs are involved in the regulation of patholog-ical process in nonalcoholic fatty liver disease(NAFLD),alco-holic fatty liver(AFL),hepatocellular carcinoma(HCC),liverregeneration and liver fibrosis mainly via antiinflammation,endocytosis,secretion of angiocrine signals and maintaining thequiescence phenotype of HSCs.This review highlights the physiological function of LSECs and the different roles in different pathological conditions,which aims to provide a new perspectivefor the treatment of liver diseases through targeting LSECs.

Aim To explore the inhibitory effect of li-gustrazine combined with paeonol on rat liver fibrosis induced by CCl4 and its mechanisms,so as to provide new treatment strategies for liver fibrosis in clinical. Methods Cleaning laboratory male SD rats were ran-domly divided into blank control group,model group (CCl4 ),ligustrazine group,paeonol group and combi-nation group (ligustrazine+paeonol).HE staining was used to observe the pathological change.Masson stai-ning and Sirius red staining was used to observe the collagen deposition.The levels of serum ALT,AST, ALP and hydroxyproline were detected by automatic bi-ochemistry analyzer.Western blot detected the markers of liver fibrosis.HSC-T6 cell was divided into model group,ligustrazine group,paeonol group and combina-tion group.The protein and gene expression of inflam-mation and apoptosis pathway was analyzed by Western blot and real time-PCR.Results Ligustrazine com-bined with paeonol could significantly improve liver tis-sue pathology changes caused by CCl4 .It could reduce serum ALT, AST, ALP and hydroxyproline levels. Moreover,it could also inhibit liver fibrosis marker protein expression,and thus reduce the deposition of collagen fibers.The effect was better than that in sin-gle intervention group.Combination group could inhib-it the inflammatory pathways related protein expression in HSC cells and promote the apoptosis of HSC cells. Conclusion Ligustrazine in combination with paeonol has significant anti-fibrosis effect,and the effect is bet-ter than both single intervention.The effect may be due to the interference with TNF-α/NF-κB pathway in the HSC cells,which promotes its apoptosis and inhib-its the generation of extracellular matrix.

Farnesoid X receptor ( FXR) plays a key role in me-tabolism of substance, such as bile acid, lipid, glucose,( etc) . Newly published credible discoveries have claimed that as a reg-ulatory hub in metabolism, FXR is closely linked with diverse chronic liver diseases, including viral hepatitis, alcoholic fatty liver disease, nonalcoholic fatty liver disease, hepatic fibrosis and hepatocellular carcinoma. This review summarizes the roles and mechanisms of FXR during the courses of chronic liver dis-eases, aiming at providing novel insights and therapeutic target for antifibrotic research and drug development.

Nicotinamide adenine dinucleotide phosphate oxidase ( NOXs) contributes to the production of reactive oxygen species ( ROS) in liver fibrosis, resulting in the activation of endoplas-mic reticulum stress ( ERS ) and IRE1α-XBP1 signaling path-way. ROS is a series of oxygen metabolites and its derivatives, produced by the single electron reduction of molecular oxygen ( O2 ) , including superoxide anion ( O2- ) , hydroxyl radical (-OH) , hydrogen peroxide ( H2 O2 ) , hypochlorite ion ( OCl-) and so on. They can interact with a large number of molecules, including small inorganic molecules, proteins, lipids, carbohy-drates and nucleic acids, resulting in lipid peroxidation of cell damaging molecules. And as a second messenger, ROS can also affect the proliferation and activation of HSC in liver fibrosis, and induce the hepatocyte apoptosis through a variety of cellular signal transduction. Here we review the current status of the study on the mechanism of NOXs in liver fibrosis.

Liver fibrosis is a major cause of morbidity and mor-tality worldwide which poses a great threat to public health. Con-siderable evidence suggests that the immune system is closely re-lated to the development of hepatic fibrosis especially the dendrit-ic cells ( DCs) . In recent years, many studies have showed that DCs play a key role in regulating the immune function of liver, which not only mediate the activation of the immune system and inflammation reaction in liver, but influence the occurrence and development of liver fibrosis. Further study has found that DCs exert different effects on liver fibrosis at different stages of the disease, and it exerts anti-fibrosis in early stages and recession period, while plays opposite effect in the middle of the disease. This article reviews the research progress of the role of DCs in liver fibrosis and discusses the underlying mechanisms of DCs in regulation of liver fibrosis, which may provide references for bas-ic and clinical studies of liver fibrosis.

MTH1 (MutT Homolog1 )as MutT homologous en-zyme,is a nucleotide pyrophosphatase,mainly involved in DNA damage repair process,especially plays an important role in the process of DNA replication in tumor cells.Recent studies have found that MTH1’s function is responsible for the development of a variety of tumors.Studies have shown that,MTH1 can remove tumor cells’oxidative DNA elements detrimental to the function-al structure,protecting tumor cell division and proliferation, maintaining tumor cell survival,however,normal cells do not need MTH1.Therefore,MTH1 may be only closely associated with abnormal cell growth.This makes MTH1 as therapeutic tar-gets that have been paid much attention.This article reviewed the relationship of MTH1 and tumor,discussed the mechanisms of MTH1 in tumor growth MTH1 and tumor treatment,so as to provide reference for clinical research and treatment of tumor.

Tumor metastasis is one of the most important biologi-cal characteristics of malignant tumor, and it is also the main factors that cause treatment failure and poor prognosis. Clinical studies have shown that the number of platelets in patients with malignant tumor increased more significantly than that in benign tumor patients and healthy people, which indicate that platelet might be involved in the development process of tumor. Further study found that in the process of cancer spreading to blood, platelet could interact with tumor cells to form tumor emboli, helped tumor cells escape from immune surveillance, thus pro-moted the tumor metastasis. In recent years, related mechanisms on platelets in promoting tumor metastasis were revealed gradual-ly, and several targeted therapies based on platelets were also carried out. This paper reviews the role of platelet in mediating tumor metastasis by hematogenous spread and its mechanisms and discusses the therapy strategies that target platelet, which may provide references for follow-up research and clinical treat-ment.