As a novel form of programmed cell death different from cell necrosis, apoptosis, and autophagy discovered in recent years, pyroptosis is characterized by cell membrane rupture and release of cell contents and proinflammatory factors mediated by gasdermin, thus leading to cell death. Pyroptosis signaling pathways can be classified into classical pathways dependent on caspase-1 and non-classical pathways dependent on caspase-4/5/11; the activation of caspase-1 in classical pathways depends on the function of inflammasome, while the direct activation of caspase-4/5/11 is observed in non-classical pathways, which leads to the lysis of gasdermin D and induce the formation of membrane pores, the maturation and release of interleukin-1β and interleukin-18, and the rupture of cell membrane to cause pyroptosis. Latest research has shown that pyroptosis plays an important role in the development and progression of chronic liver diseases. This article introduces the mechanism of pyroptosis and summarizes the role of pyroptosis in the development and progression of nonalcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, liver cirrhosis, and hepatocellular carcinoma, in order to provide new ideas and methods for the prevention and treatment of liver diseases in clinical practice.

Lysyl oxidase (LOX) family is a group of copper-containing amine oxidases composed of LOX and LOX-like proteins (LOXL1, LOXL2, LOXL3, and LOXL4). It is overexpressed in tumor tissue and promotes tumor metastasis through covalent cross-linking of extracellular matrix, with the functions of cell growth control, tumor inhibition, senescence, and chemotaxis. In recent years, more and more evidence has shown that LOX family members play a key role in the pathogenesis of hepatocellular carcinoma (HCC), suggesting that they have great potential as therapeutic targets. This article reviews the role of LOX family members in the development and progression of HCC and the intervention effect of traditional Chinese medicine extracts on HCC by regulating LOX family, in order to provide a reference for further research on the prevention and treatment of HCC.

Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA (dsDNA) sensing protein that can recognize the dsDNA released during cell disturbance and pathogen invasion and trigger the activation of inflammasome cascade. Activation of inflammasomes leads to the maturation and release of inflammatory cytokines (interleukin-1β and interleukin-18), induces pyroptosis, and initiate innate immune response. Among these inflammasomes, AIM2 and its mechanism of action and clinical significance in liver diseases has become a research hotspot at present. This article summarizes and discusses the importance of AIM2 in the pathogenesis of various liver diseases including nonalcoholic fatty liver disease, hepatitis B virus infection, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, so as to provide new ideas and a reference for clinical treatment.

Acute-on-chronic liver failure (ACLF) is a life-threatening disease with a high risk of multiple organ failure, sepsis, and death. ACLF activates innate and acquired immune responses in human body and thus leads to the progression of persistent systemic inflammatory response syndrome and multiple organ dysfunction, leading to the high mortality rate of this disease. Dysregulated immune response plays a key role in disease progression, and immunotherapy may help to target immune-mediated organ damage and inhibit the progression of liver failure. This article reviews the role and mechanism of drugs and means with a potential immune regulatory effect in ACLF, in order to provide a reference for immunotherapy for ACLF.

The development and progression of nonalcoholic fatty liver disease (NAFLD) have complex potential mechanisms. The traditional “two-hit” pathophysiological theory has been challenged, and in recent years, an increasing number of studies have been performed to investigate the interaction between insulin resistance, adipokines, and other unknown pathogenic factors in various organs. This article summarizes the factors of the liver, intestinal tract, hypothalamus, and extracellular cysts, as well as genetic factors, with an emphasis on the synergistic mechanism of action of the liver and extrahepatic organs in the pathogenesis of NAFLD, in order to provide a reference for obtaining new insights into NAFLD regulatory network and determining new targets for the prevention and treatment of NAFLD.

Sphingomyelinases (SMase) are the main enzymes that regulate the signaling pathway of sphingomyelin and the metabolism of related products, and they are involved in the key steps of the complex metabolic process of sphingomyelin. In recent years, many studies have shown that SMase is involved in the biological processes such as cell cycle arrest, cell migration, and inflammation and promotes the development and progression of hepatocellular carcinoma by regulating the apoptosis and proliferation of tumor stem cells. SMase has an important potential biological value in the development, progression, diagnosis, and treatment of hepatocellular carcinoma. This article summarizes the exact role of SMase in the development and progression of hepatocellular carcinoma, in order to provide new ideas and strategies for the clinical treatment of hepatocellular carcinoma and the development of new drugs.

Macrophages, as important immune cells, are involved in the key processes that maintain the homeostasis of intrahepatic microenvironment. Recent studies have shown that different liver diseases can induce macrophage polarization (MPP) and form M1 and M2 phenotypes with mutual antagonism. The former promotes the clearance of pathogens and inhibits tumor progression, while the latter exerts an anti-inflammatory effect and promotes tissue repair. However, there are significant differences in the mechanism of action and phenotypic switching of MPP in different liver diseases or at different pathological stages of the disease. This article focuses on the origin and polarization characteristics of intrahepatic macrophages and summarizes the research advances in the role of MPP in the pathogenesis and therapeutic drugs of non-neoplastic liver diseases such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and liver fibrosis, in order to explore the potential of MPP in regulating the immune response and inflammatory response of liver diseases.

ObjectiveTo investigate the role and possible mechanism of action of rhubarb decoction （RD） retention enema in improving inflammatory damage of brain tissue in a rat model of mild hepatic encephalopathy （MHE）. MethodsA total of 60 male Sprague-Dawley rats were divided into blank group （CON group with 6 rats） and chronic liver cirrhosis modeling group with 54 rats using the complete randomization method. After 12 weeks， 40 rats with successful modeling which were confirmed to meet the requirements for MHE model by the Morris water maze test were randomly divided into model group （MOD group）， lactulose group （LT group）， low-dose RD group （RD1 group）， middle-dose RD group （RD2 group）， and high-dose RD group （RD3 group）， with 8 rats in each group. The rats in the CON group and the MOD group were given retention enema with 2 mL of normal saline once a day； the rats in the LT group were given retention enema with 2 mL of lactulose at a dose of 22.5% once a day； the rats in the RD1， RD2， and RD3 groups were given retention enema with 2 mL RD at a dose of 2.5， 5.0， and 7.5 g/kg， respectively， once a day. After 10 days of treatment， the Morris water maze test was performed to analyze the spatial learning and memory abilities of rats. The rats were analyzed from the following aspects： behavioral status； the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） and the level of blood ammonia； pathological changes of liver tissue and brain tissue； the mRNA and protein expression levels of phosphatidylinositol 3-kinase （PI3K）， protein kinase B （AKT）， and mammalian target of rapamycin （mTOR） in brain tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the MOD group， the RD1， RD2， and RD3 groups had a significantly shorter escape latency （all P<0.01）， significant reductions in the levels of ALT， AST， IL-1β， IL-6， TNF-α， and blood ammonia （all P<0.05）， significant alleviation of the degeneration， necrosis， and inflammation of hepatocytes and brain cells， and significant reductions in the mRNA and protein expression levels of PI3K， AKT， and mTOR in brain tissue （all P<0.05）， and the RD3 group had a better treatment outcome than the RD1 and RD2 groups. ConclusionRetention enema with RD can improve cognitive function and inflammatory damage of brain tissue in MHE rats， possibly by regulating the PI3K/AKT/mTOR signaling pathway.