• 11β-Hydroxysteroid dehydrogenase type 1
• Liver fibrosis
• Metabolic dysfunction-associated steatohepatitis
• Metabolic dysfunction-associated steatotic liver disease
• Natural killer cell

• Animals
• Signal Transduction/drug effects
• Mice
• Receptors, Notch/metabolism
• Receptors, Notch/antagonists & inhibitors
• 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors
• 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism
• Male
• Mice, Inbred C57BL
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/chemically induced
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Thioacetamide/toxicity
• Enzyme Inhibitors/pharmacology

• RS-2023-00217123 National Research Foundation of Korea

• chemokines
• chronic liver failure
• cytokines
• immune response
• immunosuppression
• innate and adaptive immune response
• liver cirrhosis

• Humans
• Immunity, Innate
• Liver Failure/immunology
• Animals
• Immune System/metabolism
• Immune System/immunology
• Adaptive Immunity
• Killer Cells, Natural/immunology
• Cytokines/metabolism
• Liver/immunology
• Liver/metabolism
• Liver/pathology

• SKN No. 148 wroclaw medical university
• SUBZ.D260.24.076 wroclaw medical university

• Animals
• Female
• Humans
• Mice
• Cytokines/metabolism
• Lipids
• Liver/pathology
• Liver/parasitology
• Liver Cirrhosis/parasitology
• Mice, Inbred BALB C
• Nanoparticles/administration & dosage
• RNA, Small Interfering/genetics
• RNA, Small Interfering/administration & dosage
• Schistosoma mansoni/genetics
• Schistosomiasis mansoni

• Ministry of Science and Technology, Taiwan
• LEO Fondet
• Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics

• Hepatocellular carcinoma
• Immunosuppressive tumor microenvironment
• Immunotherapy
• Microenvironment heterogeneity

• No. 82273374 National Natural Science Foundation of China
• No. U23A20451 National Natural Science Foundation of China
• 2022CFA016 Natural Science Foundation of Hubei Province
• 2023BR038 Basic Research Support Program of Huazhong University of Science and Technology

• NAFLD
• NASH
• adipose tissue
• crosstalk
• hepatocyte
• macrophage

• Humans
• Non-alcoholic Fatty Liver Disease/pathology
• Kupffer Cells/metabolism
• Liver/pathology
• Liver/metabolism
• Hepatic Stellate Cells/metabolism
• Insulin Resistance
• Disease Progression
• Animals

• Natural Science Foundation of Sichuan Province
• 82073754 National Natural Science Foundation of China
• 82273840 National Natural Science Foundation of China
• 82304368 National Natural Science Foundation of China
• BK20221524 Natural Science Foundation of Jiangsu Province
• 2020B03003 Key R&D Program of Xinjiang Uygur Autonomous Region
• CPU2018GF08 Innovation Team of the "Double-First Class" Disciplines
• 2632023GR06 Fundamental Research Funds for the Central Universities
• 2632023TD05 Fundamental Research Funds for the Central Universities

• Fatty acids
• Fibrosis
• Hepatic stellate cells
• Immunologic factors
• Inflammation

• Humans
• Animals
• Fatty Liver/complications
• Fatty Liver/pathology
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/pathology
• Liver/pathology
• Hepatic Stellate Cells
• Fibrosis
• Disease Models, Animal

• 2021R1A2C3004589 National Research Foundation of Korea
• 2022M3A9B6017654 National Research Foundation of Korea
• RS-2023-00223831 National Research Foundation of Korea
• Ministry of Science and ICT

• Anti-fibrosis
• Cancer-associated fibroblast
• Pancreatic stellate cell
• Retinoic acid

• Mice
• Humans
• Animals
• Tretinoin/therapeutic use
• Pancreatic Stellate Cells/metabolism
• Pancreatic Stellate Cells/pathology
• Vitamin A/metabolism
• Signal Transduction
• Pancreatic Neoplasms/pathology
• Pancreatitis, Chronic/drug therapy
• Pancreatitis, Chronic/metabolism
• Pancreatitis, Chronic/pathology
• Carcinoma, Pancreatic Ductal/drug therapy

• Emerging therapies
• Immune cells
• Liver fibrosis
• Myofibroblasts
• NASH
• diagnostic advancement

• Humans
• Non-alcoholic Fatty Liver Disease/therapy
• Non-alcoholic Fatty Liver Disease/drug therapy
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver/metabolism
• Biomarkers/metabolism
• Myofibroblasts/metabolism

• NO
• TAK1
• TXNIP
• alcohol-associated liver disease
• eNOS
• liver sinusoidal endothelial cells

• Animals
• Humans
• Mice
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Cytokines/metabolism
• Endothelial Cells/metabolism
• Inflammation/metabolism
• Liver/metabolism
• Liver Cirrhosis/metabolism
• Liver Diseases, Alcoholic/genetics
• Liver Diseases, Alcoholic/metabolism
• Nitric Oxide/metabolism

• Humans
• Non-alcoholic Fatty Liver Disease/metabolism
• Immunity, Innate
• Lymphocytes/pathology
• Liver/metabolism
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Inflammation/pathology
• Fibrosis

• Active ingredient
• Anti-hepatic fibrotic therapy
• Chinese herbal medicine
• Liver fibrosis
• Molecular mechanism

• Humans
• Drugs, Chinese Herbal/therapeutic use
• Fibrosis
• Liver Diseases/drug therapy
• Treatment Outcome
• Liver Cirrhosis/drug therapy

• cellular and molecular mechanisms
• hepatic stellate cells
• liver fibrosis
• natural killer cells
• treatments

• R01 CA208396 NCI NIH HHS
• R01 CA250536 NCI NIH HHS
• R01CA208396 NIH HHS
• R01DK130340 NIH HHS
• R01CA250536 NIH HHS

• Humans
• Cholangitis, Sclerosing
• Mast Cells/pathology
• Immunity, Innate
• Lymphocytes/pathology
• Liver/pathology
• Cholestasis
• Liver Cirrhosis/pathology
• Inflammation
• Liver Cirrhosis, Biliary

• IK6BX005226 Hickam Endowed Chair, Gastroenterology, Medicine, Indiana University, the Indiana University Health - Indiana University School of Medicine Strategic Research Initiative
• 1I01BX003031 Hickam Endowed Chair, Gastroenterology, Medicine, Indiana University, the Indiana University Health - Indiana University School of Medicine Strategic Research Initiative
• DK108959 United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service
• DK119421 United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service

• Innate immune response
• liver fibrosis
• metabolic syndrome
• metabolic-associated fatty liver disease
• nonalcoholic fatty liver disease

• gene polymorphism
• inflammatory factors
• liver cirrhosis
• meta-analysis
• systematic review

• ADH inhibitor
• Alcohol dehydrogenase
• Hepatic stellate cell
• Liver fibrosis

• Animals
• Mice
• Carbon Tetrachloride/toxicity
• Disease Models, Animal
• Hepatic Stellate Cells/metabolism
• Liver/metabolism
• Liver Cirrhosis/pathology
• Transforming Growth Factor beta1/metabolism
• Alcohol Dehydrogenase/metabolism

• bioluminescence imaging (BLI)
• carbon tetrachloride (CCl4)
• liver cirrhosis
• natural killer (NK) cells

• NRF-2020R1A2C2011695 National Research Foundation of Korea
• 2020R1A2C2011428 National Research Foundation of Korea
• 2022R1F1A1069854 National Research Foundation of Korea

• Hepatic fibrosis
• microenvironment
• therapy

• Acute bacterial peritonitis
• Bacterial infection
• Liver injury
• MCPIP-1
• Neutrophils

• Humans
• Animals
• Mice
• Mice, Inbred C57BL
• Ribonucleases/metabolism
• Neutrophils/cytology
• Neutrophils/metabolism
• Peritonitis/immunology
• Peritonitis/metabolism
• Peritonitis/microbiology
• Salmonella typhimurium/physiology
• Salmonella Infections/immunology
• Salmonella Infections/metabolism
• Reactive Oxygen Species/metabolism
• Peroxidase/metabolism
• Down-Regulation
• Extracellular Traps
• Cell Movement
• Liver/injuries
• Liver/metabolism
• Liver/pathology
• Killer Cells, Natural/metabolism
• RNA-Binding Proteins/metabolism
• Immune Tolerance

Cancer is a complex disease, and despite incredible progress over the last decade, it remains the leading cause of death worldwide. Liver cancers, including hepatocellular carcinoma (HCC), and liver metastases are distinct from other cancers in that they typically emerge as a consequence of long-term low-grade inflammation. Understanding the mechanisms that underpin inflammation-driven tissue remodeling of the hepatic immune environment is likely to provide new insights into much needed treatments for this devastating disease. Group 1 innate lymphoid cells (ILCs), which include natural killer (NK) cells and ILC1s, are particularly enriched in the liver and thought to contribute to the pathogenesis of a number of liver diseases, including cancer. NK cells are an attractive, but underexplored, therapeutic target in hepatic disease due to their role in immunosurveillance and their ability to recognize and eliminate malignant cells. ILC1s are closely related to and share many phenotypic features with NK cells but are less well studied. Thus, their utility in immunotherapeutic approaches is not yet well understood. Here, we review our current understanding of ILCs in cancer with a particular focus on liver and liver-related diseases.

Liver fibrosis is a highly conserved wound healing response to liver injury, characterized by excessive deposition of extracellular matrix (ECM) in the liver which might lead to loss of normal functions. In most cases, many types of insult could damage hepatic parenchymal cells like hepatocytes and/or cholangiocytes, and persistent injury might lead to initiation of fibrosis. This process is accompanied by amplified inflammatory responses, with immune cells especially macrophages recruited to the site of injury and activated, in order to orchestrate the process of wound healing and tissue repair. In the liver, both resident macrophages and recruited macrophages could activate interstitial cells which are responsible for ECM synthesis by producing a variety of cytokines and chemokines, modulate local microenvironment, and participate in the regulation of fibrosis. In this review, we will focus on the main pathological characteristics of liver fibrosis, as well as the heterogeneity on origin, polarization and functions of hepatic macrophages in the setting of liver fibrosis and their underlying mechanisms, which opens new perspectives for the treatment of liver fibrosis.

• Fibrosis
• Humans
• Kupffer Cells
• Liver Cirrhosis
• Macrophages

Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.

• Endoplasmic Reticulum Stress/physiology
• Humans
• Immunity, Innate
• Inflammation/metabolism
• Liver Cirrhosis/complications
• Liver Neoplasms
• Non-alcoholic Fatty Liver Disease/pathology

Liver fibrosis is a common pathological process of chronic liver diseases, including viral hepatitis and alcoholic liver disease, and ultimately progresses to irreversible cirrhosis and cancer. Hepatic stellate cells (HSCs) are activated to produce amounts of collagens in response to liver injury, thus triggering the initiation and progression of fibrogenesis. Natural killer (NK) cells serve as the essential component of hepatic innate immunity and are considered to alleviate fibrosis by killing activated HSCs. Current antifibrotic interventions have improved fibrosis, but fail to halt its progression in the advanced stage. Clarifying the interaction between NK cells and HSCs will provide clues to the pathogenesis and potential therapies for advanced liver fibrosis.

• TGF‑β
• crosstalk
• fibrosis
• hepatic stellate cells
• natural killer cells

• Autoimmune hepatitis
• Cytokines
• Immune inhibition
• Therapy

• Animals
• CD8-Positive T-Lymphocytes
• Hepatitis, Autoimmune/drug therapy
• Humans
• Interleukin-10
• Interleukin-2/therapeutic use
• Transforming Growth Factor beta
• Transforming Growth Factors/therapeutic use

• alcohol-associated liver disease
• hepatocellular carcinoma
• liver steatosis
• nonalcoholic fatty liver disease
• retinoic acid
• retinoic acid receptor
• vitamin A

• Humans
• Liver Diseases/drug therapy
• Liver Diseases/etiology
• Receptors, Retinoic Acid/metabolism
• Retinoids/metabolism
• Tretinoin/therapeutic use
• Vitamin A/therapeutic use

• R01 DK113088 NIDDK NIH HHS
• T32 CA062948 NCI NIH HHS
• 5SC2GM127206-0 NIGMS NIH HHS
• R21 AA027637 NIAAA NIH HHS
• R01DK113088 NIDDK NIH HHS

• chronic liver diseases
• liver fibrosis
• nanomedicine
• nanotechnology
• targeted drug delivery

Natural killer (NK) cells play a therapeutic role in liver fibrosis (LF). We aimed to analyze NK cells in heavy drinkers without cirrhosis or decompensated liver disease and establish correlations with other related subpopulations. Data on sociodemographic characteristics, alcohol consumption, laboratory parameters, and immunophenotyping of NK (CD16⁺/CD56⁺), T (CD3⁺), B (CD19⁺), NKT (CD16⁺/CD56⁺/CD3⁺), and cytotoxic (CD3^-CD8⁺) cells were collected. Fibrosis-4 (FIB-4) scores were used to compare patients without (FIB-4 < 1.45) and with (FIB-4 > 3.25) advanced LF (ALF). We included 136 patients (76% male) with a mean age of 49 years who had a 15-year alcohol use disorder (AUD) and alcohol consumption of 164 g/day. Patients with ALF (n = 25) presented significantly lower absolute total lymphocyte, T cell, B cell, and NKT cell numbers than patients without LF (n = 50; p < 0.01). However, the NK cells count was similar (208 ± 109 cells/µL vs. 170 ± 105 cells/µL) in both groups. The T cells percentage was lower (80.3 ± 5.6% vs. 77 ± 7%; p = 0.03) and the NK cells percentage was higher (9.7 ± 5% vs. 13 ± 6%; p = 0.02) in patients with ALF than in those without LF. The percentages of NK cells and T cells were inversely correlated in patients without (r = –0.65, p < 0.01) and with ALF (r = −0.64; p < 0.01). Additionally, the NK cells and CD3^-CD8⁺ cell percentages were positively correlated in patients without (r = 0.87, p < 0.01) and with (r = 0.92; p < 0.01) ALF. Conclusions: Heavy drinkers without decompensated liver disease showed an increase in NK cells related to T cells lymphopenia and an increase in cytotoxic populations. The interaction of NK cells with other subpopulations may modify alcohol-related liver disease progression.

• FIB-4 score
• alcohol liver disease
• lymphocyte population

Fibrosis is a major player and contributor in the tumor microenvironment. Profibrotic changes precede the early development and establishment of a variety of human diseases, such as fibrosis and cancer. Being able to measure such early signals at the single cell level is critically useful for identifying new mechanisms and potential drug targets for a wide range of diseases. This study was designed to computationally identify profibrotic cell populations using single-cell transcriptomic data and to identify gene signatures that could predict cancer prognosis.

Fibrosis is a major cause of mortality. Key profibrotic mechanisms are common pathways involved in tumorigenesis. Characterizing the profibrotic phenotype will help reveal the underlying mechanisms of early development and progression of a variety of human diseases, such as fibrosis and cancer. Fibroblasts have been center stage in response to various stimuli, such as viral infections. However, a comprehensive catalog of cell types involved in this process is currently lacking. Here, we deployed single-cell transcriptomic data across multi-organ systems (i.e., heart, kidney, liver, and lung) to identify novel profibrotic cell populations based on ECM pathway activity at single-cell resolution. In addition to fibroblasts, we also reported that epithelial, endothelial, myeloid, natural killer T, and secretory cells, as well as proximal convoluted tubule cells of the nephron, were significantly actively involved. Cell-type-specific gene signatures were enriched in viral infection pathways, enhanced glycolysis, and carcinogenesis, among others; they were validated using independent datasets in this study. By projecting the signatures into bulk TCGA tumor samples, we could predict prognosis in the patients using profibrotic scores. Our profibrotic cellular phenotype is useful for identifying new mechanisms and potential drug targets at the cell-type level for a wide range of diseases involved in ECM pathway activation.

• cancer prognosis
• fibrosis
• pan-cancer
• profibrotic cellular phenotype
• single-cell extracellular matrix pathway activity

• biomarkers
• diabetes mellitus
• hepatocellular carcinoma
• metabolic syndrome
• non-alcoholic fatty liver disease
• screening programs
• ultrasound

Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.

• ECM degradation
• HSCs
• fibrosis regression
• liver fibrosis
• myofibroblasts
• therapies

• Animals
• Extracellular Matrix/metabolism
• Humans
• Inflammation/pathology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Cirrhosis/physiopathology
• Myofibroblasts/pathology
• Remission Induction
• Vascular Remodeling

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8⁺ tissue-resident memory CD8⁺ T (CD8⁺ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69⁺CD103⁻CD8⁺ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8⁺ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8⁺ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69⁺CD8⁺ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8⁺ Trm in fibrosis resolution.

The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.

Hepatitis C virus (HCV)-related cirrhosis leads to a heavy global burden of disease. Clinical risk stratification in HCV-related compensated cirrhosis remains a major challenge. Here, we aim to develop a signature comprised of immune-related genes to identify patients at high risk of progression and systematically analyze immune infiltration in HCV-related early-stage cirrhosis patients. Bioinformatics analysis was applied to identify immune-related genes and construct a prognostic signature in microarray data set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted with the “clusterProfiler” R package. Besides, the single sample gene set enrichment analysis (ssGSEA) was used to quantify immune-related risk term abundance. The nomogram and calibrate were set up via the integration of the risk score and clinicopathological characteristics to assess the effectiveness of the prognostic signature. Finally, three genes were identified and were adopted to build an immune-related prognostic signature for HCV-related cirrhosis patients. The signature was proved to be an independent risk element for HCV-related cirrhosis patients. In addition, according to the time-dependent receiver operating characteristic (ROC) curves, nomogram, and calibration plot, the prognostic model could precisely forecast the survival rate at the first, fifth, and tenth year. Notably, functional enrichment analyses indicated that cytokine activity, chemokine activity, leukocyte migration and chemotaxis, chemokine signaling pathway and viral protein interaction with cytokine and cytokine receptor were involved in HCV-related cirrhosis progression. Moreover, ssGSEA analyses revealed fierce immune-inflammatory response mechanisms in HCV progress. Generally, our work developed a robust prognostic signature that can accurately predict the overall survival, Child-Pugh class progression, hepatic decompensation, and hepatocellular carcinoma (HCC) for HCV-related early-stage cirrhosis patients. Functional enrichment and further immune infiltration analyses systematically elucidated potential immune response mechanisms.

• cirrhosis
• hepatitis C virus
• immune microenvironment
• prediction
• prognosis

Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.

• epigallocatechin gallate
• green tea
• multiple parallel hits
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• oxidative stress
• reactive oxygen species
• redox homeostasis

• Animals
• Anti-Inflammatory Agents/pharmacology
• Apoptosis/drug effects
• Cyclooctanes/pharmacology
• Inflammasomes/drug effects
• Lignans/pharmacology
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/parasitology
• Male
• Mice
• Mice, Inbred BALB C
• Polycyclic Compounds/pharmacology
• RAW 264.7 Cells
• Schistosoma mansoni/drug effects
• Schistosomiasis mansoni/drug therapy
• Spleen/drug effects
• Spleen/parasitology

• apoptosis
• cellular senescence
• fate
• fibrosis
• myofibroblast
• plasticity
• reprogramming
• tissue repair

This study investigated the mechanisms underlying the preventive effect of dihydromyricetin (DHM) against liver fibrosis involving hepatic stellate cells (HSCs) and hepatic natural killer (NK) cells.

A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in C57BL/6 mice to study the antifibrotic effect of DHM based on serum biochemical parameters, histological and immunofluorescence stainings, and the expression of several fibrosis-related markers. Based on the immunoregulatory role of DHM, the effect of DHM on NK cell activation ex vivo was evaluated by flow cytometry. Then, we investigated whether DHM-induced autophagy was involved in HSCs inactivation using enzyme-linked immunosorbent assays, transmission electron microscopy, and western blot analysis. Thereafter, the role of DHM in NK cell-mediated killing was studied by in vitro coculture of NK cells and HSCs, with subsequent analysis by flow cytometry. Finally, the mechanism by which DHM regulates NK cells was studied by western blot analysis.

DHM ameliorated liver fibrosis in C57BL/6 mice, as characterized by decreased serum alanine transaminase and aspartate transaminase levels, decreased expressions of collagen I alpha 1 (CoL-1α1), collagen I alpha 2 (CoL-1α2), tissue inhibitor of metalloproteinases 1 (TIMP-1), α-smooth muscle actin (α-SMA) and desmin, as well as increased expression of matrix metalloproteinase 1 (MMP1). Interestingly, HSCs activation was significantly inhibited by DHM in vivo and in vitro. As expected, DHM also upregulated autophagy-related indicators in liver from CCl₄-treated mice. DHM also prevented TGF-β1-induced activation of HSCs in vitro by initiating autophagic flux. In contrast, the autophagy inhibitor 3-methyladenine markedly abolished the antifibrotic effect of DHM. Surprisingly, the frequency of activated intrahepatic NK cells was significantly elevated by DHM ex vivo. Furthermore, DHM enhanced NK cell-mediated killing of HSCs by increasing IFN-γ expression, which was abolished by an anti-IFN-γ neutralizing antibody. Mechanistically, DHM-induced IFN-γ expression was through AhR-NF-κB/STAT3 pathway in NK cells.

These results demonstrated that DHM can ameliorate the progression of liver fibrosis and inhibition of HSCs activation by inducing autophagy and enhancing NK cell-mediated killing through the AhR-NF-κB/STAT3-IFN-γ signaling pathway, providing new insights into the preventive role of DHM in liver fibrosis.

The online version contains supplementary material available at 10.1186/s12986-021-00589-6.

• Dihydromyricetin
• Hepatic stellate cells
• IFN-γ
• Liver fibrosis
• Natural killer cells

Liver fibrosis is a pathological process caused by persistent chronic injury of the liver. Kupffer cells, natural killer (NK) cells, NKT cells, and dendritic cells (DCs), which are in close contact with T and B cells, serve to bridge innate and adaptive immunity in the liver. Meanwhile, an imbalanced inflammatory response constitutes a challenge in liver disease. The dichotomous roles of novel immune cells, including T helper 17 (Th17), regulatory T cells (Tregs), mucosa-associated invariant T cells (MAIT), and innate lymphoid cells (ILCs) in liver fibrosis have gradually been revealed. These cells not only induce damage during liver fibrosis but also promote tissue repair. Hence, immune cells have unique, and often opposing, roles during the various stages of fibrosis. Due to this heterogeneity, the treatment, or reversal of fibrosis through the target of immune cells have attracted much attention. Moreover, activation of hepatic stellate cells (HSCs) constitutes the core of fibrosis. This activation is regulated by various immune mediators, including Th17, Th22, and Th9, MAIT, ILCs, and γδ T cells, as well as their related cytokines. Thus, liver fibrosis results from the complex interaction of these immune mediators, thereby complicating the ability to elucidate the mechanisms of action elicited by each cell type. Future developments in biotechnology will certainly aid in this feat to inform the design of novel therapeutic targets. Therefore, the aim of this review was to summarize the role of specific immune cells in liver fibrosis, as well as biomarkers and treatment methods related to these cells.

• T helper cells
• hepatic stellate cells
• innate lymphoid cells
• liver fibrosis
• mucosa-associated invariant T cells
• regulatory T cells

Hepatocellular carcinoma (HCC) is a highly lethal and complex malignancy strongly influenced by the surrounding tumor microenvironment. The HCC microenvironment comprises hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), stromal and endothelial cells, and the underlying extracellular matrix (ECM). Emerging evidence demonstrates that epigenetic regulation plays a crucial role in altering numerous components of the HCC tumor microenvironment. In this review, we summarize the current understanding of the mechanisms of epigenetic regulation of the microenvironment in HCC. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation, histone regulation, and non-coding RNAs mediated regulation) in HSCs, TAMs, and ECM, and how they contribute to HCC development, so as to gain new insights into the treatment of HCC via regulating epigenetic regulation in the tumor microenvironment.

• DNA methylation
• extracellular matrix
• hepatic stellate cells
• histone deacetylases
• histone methyltransferases
• microRNAs
• tumor microenvironment
• tumor-associated macrophages

• HCV
• HCC
• HIV
• direct-acting antivirals
• fibrogenesis

• Disease Progression
• Female
• HIV Infections/complications
• HIV Infections/virology
• Hepatitis C/complications
• Hepatitis C/virology
• Humans
• Liver Diseases/mortality
• Liver Diseases/pathology
• Liver Diseases/virology
• Male
• Mortality
• RNA Viruses/genetics
• Sustained Virologic Response

• R01 AI136715 NIAID NIH HHS
• National Institutes of Health

• HBV
• HCC
• HCV
• extracellular matrix (ECM)
• hepatic fibrosis
• hepatic stellate cells (HSCs)
• liver

• Cytokines/physiology
• Extracellular Matrix/physiology
• Hepatitis, Viral, Human/complications
• Humans
• Liver/cytology
• Liver Cirrhosis/etiology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/immunology
• Liver Cirrhosis/therapy
• Liver Diseases, Alcoholic/complications
• Polymorphism, Genetic

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

• fibrosis
• hepatic stellate cells
• hepatocellular carcinoma
• hepatocytes
• inflammation
• tumor microenvironment

• bioflavonoids
• cholangiocytes
• hepatic stellate cells
• herbal
• phytochemicals
• primary sclerosing cholangitis

• Cholangiopaties
• Genetic factors
• Hypoxia-inducible factors
• Liver fibrogenesis
• Macrophages
• Myofibroblasts