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Aim
Fibrosis is a common pathological feature of most types of chronic liver injuries. There is no specific treatment for liver fibrosis at present. The liver microenvironment, which fosters the survival and activity of liver cells, plays an important role in maintaining the normal structure and physiological function of the liver. The aim of this...
Citations
... Moreover, other immune cells different from KC would also help to better mimic the immune-mediated pathomechanisms in MASLD and liver fibrosis (Bronsard et al., 2024). It is clear that multicellular interaction within a pro-fibrotic microenvironment leads to liver fibrosis, thus a key issue to achieve the reversal of liver fibrosis may be the restoration of microenvironmental homeostasis, which could help all types of liver cells to maintain a more stable and long-lasting state and prevent liver cells from changing into a profibrotic state (Meng et al., 2022). In this sense, the identification of reliable biomarkers of fibrosis in vitro would help to clearly make a step forward in the translation to the clinical setting. ...
Liver fibrosis has been proposed as the most important predictive indicator affecting prognosis of patients with chronic liver disease. It is defined by an abnormal accumulation of extracellular matrix components that results from necrotic and inflammatory processes and eventually impairs organ function. With no approved therapy, comprehensive cellular models directly derived from patient’s cells are necessary to understand the mechanisms behind fibrosis and the response to anti-fibrotic therapies. Primary human cells, human hepatic cell lines and human stem cells-derived hepatic stellate-like cells have been widely used for studying fibrosis pathogenesis. In this paper, we depict the cellular crosstalk and the role of extracellular matrix during fibrosis pathogenesis and summarize different in vitro models from simple monolayers to multicellular 3D cultures used to gain deeper mechanistic understanding of the disease and the therapeutic response, discussing their major advantages and disadvantages for liver fibrosis modelling.
... Moreover, TGF-β1-induced increased levels of ROS and 8-OHdG, a DNA damage marker, were inhibited by circABHD3 knockdown (Fig 2D and 2E). In addition, hepatic fibrosis is associated with mitochondrial dysfunction, which can lead to hepatocyte damage, immune cell activation, inflammation, and trans-differentiation of hepatic stellate cells [30][31][32]. We found that TGF-β1-induced increased JC-1 monomer and decreased JC-1 aggregate in TGF-β1-treated THLE-2 and AML12 cells were reduced by circABHD3 knockdown, suggesting that circABHD3 knockdown suppressed TGF-β1-induced impaired mitochondrial membrane potential (Fig 2F). ...
Background
Hepatic fibrosis may progress to liver cirrhosis and eventually cause death. Epithelial-mesenchymal transition (EMT) of hepatocytes plays critical roles in hepatic fibrosis. Exploring the mechanisms underlying EMT is crucial for a better understanding of hepatic fibrosis pathogenesis.
Methods
Hepatocyte EMT wad induced with TGF-β1 and evaluated by Western blotting and immunofluorescence staining. Methylated RNA immunoprecipitation (MeRIP) was applied to assess N6-methyladenosine (m6A) modification. RIP and RNA pull-down assays were performed to analyze the interaction between circABHD3, YTHDF2 and YPEL3 mRNA. MEOX1-mediated transcription of ABHD3 was examined by luciferase and chromatin immunoprecipitation (ChIP). Mice were intraperitoneally injected with CCl4 or treated with bile duct ligation (BDL) surgery for hepatic fibrosis induction. Liver injury and collagen deposition were examined with hematoxylin and eosin (HE), Masson, and Sirius Red staining. Alanine transaminase (ALT), aspartate transaminase (AST) and hydroxyproline (HYP) were examined using ELISA.
Results
CircABHD3 was upregulated in in vitro and in vivo models of hepatic fibrosis and patients. Knockdown of circABHD3 inhibited TGF-β1-induced expression of fibrosis markers, EMT and mitochondrial impairment in hepatocytes. MEOX1 could directly bind to the promoter of ABHD3 to facilitate its transcription and subsequent circABHD3 generation. Knockdown of MEOX1 suppressed TGF-β1-induced EMT and mitochondrial impairment through suppression of circABHD3. CircABHD3 destabilized YPEL3 mRNA via promoting YTHDF2-dependent recognition of m6A-modified YPEL3 mRNA to trigger β-catenin signaling activation. Furthermore, circABHD3 silencing-mediated inhibition of EMT and mitochondrial impairment was counteracted by YPEL3 knockdown and activation of β-catenin signaling. Depletion of circABHD3 significantly reduced EMT, mitochondrial impairment and hepatic fibrosis via promoting YPEL3 expression and suppressing β-catenin signaling in vivo.
Conclusion
MEOX1-mediated generation of circABHD3 promotes EMT and mitochondrial impairment by enhancing YTHDF2-mediated degradation of YPEL3 mRNA and activating downstream β-catenin signaling, thus exacerbating hepatic fibrosis.
... The liver microenvironment plays an important role in the formation of liver fibrosis. Factors such as the presence of inflammatory cells, particularly macrophages, and the ECM's composition can also significantly influence HSC activation and proliferation [21]. During liver injury, activated hepatic stellate cells (HSCs), macrophages, endothelial cells, and hepatocytes produce the platelet-derived growth factor (PDGF), which plays a key role in liver fibrosis. ...
... Among these, serum biomarkers such as hyaluronic acid, collagen type IV, and tissue inhibitors of metalloproteinases (TIMPs) have garnered attention due to their association with liver histology. For example, elevated levels of hyaluronic acid are linked to hepatic inflammation and fibrosis, suggesting its potential as a marker for liver disease progression [21]. Moreover, the role of hepatic macrophages in fibrosis development indicates that their activity could also serve as a marker for liver fibrosis [17]. ...
Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.
... MCP-1 is one of the key cytokines that regulates the migration and infiltration of monocytes/macrophages, which initiates further inflammatory cellular responses (Tedgui and Mallat, 2006). MCP-1 is induced and secreted in endothelial cells stimulated by TNF-α (Meng et al., 2022). Therefore, we tested whether AT or ATF prevented TNF-α-induced MCP-1. ...
... Recently, we reported that AT significantly blocked cholestasis-induced liver damage via the inhibition of inflammation and fibrosis (Bae et al., 2022). In hepatic diseases such as hepatitis and cirrhosis, elevated systemic and hepatic TNF-α levels have been linked to vascular dysfunction (Meng et al., 2022). Endothelial cells in a vessel are a major component cell type involved in vascular function since they act as the first barrier against injury (Kitada et al., 2016). ...
... NF-κB is a key transcriptional factor that regulates inflammatory genes (Liu et al., 2017). The NF-κB motif in the promoters of ICAM-1, VCAM-1, and MCP-1 is particularly important for the induction of these genes (Rothgiesser et al., 2010;Meng et al., 2022). AT and ATF inhibited the TNF-α-induced nuclear translocation and transcriptional activity of NF-κB. ...
Acer tegmentosum Maxim (AT) is a medicinal plant used to treat hepatic, neurological diseases, and cancer. However, the beneficial effects of AT on endothelial dysfunction have not been reported yet. In this study, we evaluated the effects of AT and the main compounds against TNF-α-mediated inflammatory responses and their possible mechanism of action. The anti-inflammatory effect and its molecular mechanism were analyzed by adhesion assay, immunoblotting, promoter-luciferase assay, ELISA, RT-PCR, immunocytochemistry, immunoprecipitation, siRNA gene knockdown, docking, and molecular dynamics simulation. AT and its compounds salidroside and tyrosol reduced TNF-α-induced adhesion between monocytes and endothelial cells. Fermentation of AT with Bacillus subtilis converted salidroside to tyrosol, which is salidroside’s aglycone. The fermented AT product (ATF) potently inhibited TNF-α-mediated monocyte adhesion with higher potency than AT. AT or ATF abrogated TNF-α-induced expression of adhesion molecules (VCAM-1 and ICAM-1) and production of MCP-1 with the inhibition of phosphorylated MAP kinases. TNF-α-mediated NF-κB transactivation and RelA/p65 acetylation were suppressed by AT and ATF through the interaction of NF-κB with sirtuin-1 (SIRT1), an NAD⁺-dependent histone deacetylase. Sirt1 gene knockdown diminished the protective effects of AT and ATF against TNF-α-mediated signaling and inflammatory response. Interestingly, SIRT1 protein expression was significantly increased by ATF and tyrosol rather than by AT and salidroside, respectively. Molecular docking showed that the tyrosol moiety is critical for the interaction with Glu²³⁰ of SIRT1 (PDB ID: 4ZZH and 4ZZJ) for the deacetylase activity. Molecular dynamics revealed that tyrosol can induce the movement of the N-terminal domain toward the catalytic domain of SIRT1. This study demonstrates the potential of AT and ATF to prevent endothelial inflammation and vascular dysfunction of the retina by the MAPK/NF-κB/SIRT1 signaling pathways and targeting of the tyrosol moiety to Glu²³⁰ in SIRT1.
... Given the mixed success of mitochondrial inhibitors in clinical settings across various cancer types, how can we design effective therapies targeting mitochondrial processes in HCC? This is particularly challenging due to the liver's highly adaptive and responsive nature to its microenvironment (Meng et al., 2022). An unexamined approach to targeting mitochondrial metabolism in HCC treatment could be to amplify an existing cellular stress rather than creating a synthetic vulnerability. ...
Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease‐related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism‐specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria‐focused therapeutics.
... It stands as the common endpoint of all chronic liver diseases, marked by the overproduction of extracellular matrix (ECM) proteins. This overproduction results in damage to liver cells and the creation of fibrotic scars [33,34]. Without the removal of these causative factors, fibrosis can progress to cirrhosis, the most advanced stage of liver disease. ...
Fibrosis, a significant health issue linked to chronic inflammatory diseases, affects various organs and can lead to serious damage and loss of function. Despite the availability of some treatments, their limitations necessitate the development of new therapeutic options. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for their glucose-lowering ability, have shown promise in offering protective effects against fibrosis in multiple organs through glucose-independent mechanisms. This review explores the anti-fibrotic potential of SGLT2i across different tissues, providing insights into their underlying mechanisms and highlighting recent research advancements. The evidence positions SGLT2i as a potential future treatments for fibrotic diseases.
... This unique, complex, and highly dynamic region is rich in growth or signaling factors [73]. These different cell types and ECM proteins can coordinate liver remodeling, hematopoiesis, immune function, and tissue regeneration, which may be potential targets for the treatment of liver fibrosis [74,75]. ...
Objective
This study investigated the role of long non-coding RNAs (lncRNAs) FTX in vascular endothelial cells (ECs).
Methods
Transfection of FTX/Sh-FTX with lentivirus was used to construct gain and loss of function cell models in human umbilical vein endothelial cells (HUVECs). Liquid chromatography-mass spectrometry was used for quantitative proteomics analysis of differentially expressed proteins (DEPs). Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein interaction analysis were further conducted to investigate the key molecules and pathways that respond to lncRNA-FTX.
Results
In the proteomics analysis, 3308 quantifiable proteins were identified, 64 proteins were upregulated and 103 were downregulated when lncRNA FTX was overexpressed. Additionally, 100 proteins were upregulated and 147 were downregulated when lncRNA FTX was knocked down. Functional clustering analysis of DEPs demonstrated that lncRNA FTX was involved in multiple biological processes. Among them, the expression of complement 3 (C3), cartilage oligomeric matrix protein (COMP), faciogenital dysplasia 6 (FGD6), and tissue inhibitor of metalloproteinase 1 (TIMP1) was significantly upregulated when lncRNA FTX was knocked down, and significantly downregulated when lncRNA FTX was overexpressed. They are associated with inflammation, collagen deposition, angiogenesis, and regulation of liver stem cell differentiation, which may be associated with the occurrence and development of liver fibrosis.
Conclusions
The study demonstrated that lncRNA FTX might play a potential role in ECs and contribute to the development of liver fibrosis. Thus, FTX may be a promising target for the prevention or reversal of liver fibrosis.
... Therefore, the search for effective diagnostic biomarkers of HBV-LC is of great clinical value to improve its prognosis and to explore the underlying mechanisms of its formation. Cirrhosis during the transformation of CHB to HBV-LC is the result of cytopathic adaptation, where liver parenchymal cells and non-parenchymal cells undergo functional changes to adapt to the disrupted liver microenvironment (Bi and Ge, 2014;Dash et al., 2020;Meng et al., 2022). Therefore, this study attempts to screen diagnostic biomarkers of HBV-LC by high-throughput sequencing technology with bioinformatics approach and to investigate the changes that occur during the progression of CHB to HBV-LC. ...
Background: Hepatitis B-related liver cirrhosis (HBV-LC) is a common clinical disease that evolves from chronic hepatitis B (CHB). The development of cirrhosis can be suppressed by pharmacological treatment. When CHB progresses to HBV-LC, the patient’s quality of life decreases dramatically and drug therapy is ineffective. Liver transplantation is the most effective treatment, but the lack of donor required for transplantation, the high cost of the procedure and post-transplant rejection make this method unsuitable for most patients.
Methods: The aim of this study was to find potential diagnostic biomarkers associated with HBV-LC by bioinformatics analysis and to classify HBV-LC into specific subtypes by consensus clustering. This will provide a new perspective for early diagnosis, clinical treatment and prevention of HCC in HBV-LC patients. Two study-relevant datasets, GSE114783 and GSE84044, were retrieved from the GEO database. We screened HBV-LC for feature genes using differential analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning algorithms including least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) for a total of five methods. After that, we constructed an artificial neural network (ANN) model. A cohort consisting of GSE123932, GSE121248 and GSE119322 was used for external validation. To better predict the risk of HBV-LC development, we also built a nomogram model. And multiple enrichment analyses of genes and samples were performed to understand the biological processes in which they were significantly enriched. And the different subtypes of HBV-LC were analyzed using the Immune infiltration approach.
Results: Using the data downloaded from GEO, we developed an ANN model and nomogram based on six feature genes. And consensus clustering of HBV-LC classified them into two subtypes, C1 and C2, and it was hypothesized that patients with subtype C2 might have milder clinical symptoms by immune infiltration analysis.
Conclusion: The ANN model and column line graphs constructed with six feature genes showed excellent predictive power, providing a new perspective for early diagnosis and possible treatment of HBV-LC. The delineation of HBV-LC subtypes will facilitate the development of future clinical treatment of HBV-LC.
... The liver microenvironment, which fosters the survival and activity of liver cells, plays an important role in maintaining the normal structure and physiological function of the liver. The homeostasis of the liver microenvironment is disrupted during liver fibrosis development, causing hepatocyte damage, LSECs capillarization, HSCs activation, macrophage polarization, and immune cell suppression, and changing the cell-cell and cell-matrix interactions, which eventually form the hepatic fibrotic microenvironment [7,8]. Recent studies have shown that modest prognostic performance (area under the receiver operating characteristic curve from 0.54 to 0.71) of five indirect markers of fibrosis (aspartate aminotransferase [AST]to-platelet ratio index [APRI], Fibrosis-4 Index [FIB-4], BARD, Forns, NAFLD score [NAS]) [9] and direct markers-Liver Fibrosis test (LF) [10] to predict future development of cirrhosis and severe liver disease in the general population. ...
Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed.
Graphical Abstract
