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Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis). Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.

The nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine-monophosphate (cGMP) pathway is impaired in liver fibrosis. We investigated expression patterns of NO-sGC-cGMP components via RT-qPCR in various rat models of liver fibrosis and murine models of liver fibrosis regression. Hepatic cGMP-levels were measured chromatographically. All models demonstrated portal-hypertension and liver fibrosis, which significantly regressed in murine models. The rat models showed etiology-specific differences in NO-sGC-cGMP pathway regulation. We observed strong upregulation of sGCa1 and sGCb1 subunits in a rat choline-deficient high-fat diet model (1.75-fold, p  = 0.004 and 2.04-fold, p  = 0.004, respectively). The sGCa2 subunit was markedly downregulated in a rat thioacetamide model (0.66-fold, p  = 0.026). The rat bile-duct-ligation model was characterized by strong upregulation of inducible nitric oxide synthetase (28.10-fold, p  = 0.029). The rat thioacetamide and bile-duct-ligation models displayed downregulation of sGCb2 (0.15-fold, p  = 0.002, and 0.19-fold, p  = 0.029, respectively). Regardless, hepatic cGMP-levels in rat models remained unchanged. Both mouse models demonstrated upregulation of NO-sGC-cGMP pathway nodes during regression, further accompanied by increased hepatic cGMP-levels in murine carbon tetrachloride (peak-fibrosis: 3.86 nM vs. 1-week regression: 6.28 nM, p  = 0.006; vs. 2-week regression: 5.49 nM, p  = 0.091) and thioacetamide (peak-fibrosis: 2.87 nM vs. 1-week regression: 5.22 nM, p  = 0.007; vs. 2-week regression: 6.68 nM, p  < 0.001) models. The NO-sGC-cGMP pathway exhibits etiology-specific and temporal regulation patterns during liver fibrogenesis and fibrosis regression. We further highlight the functional contribution of the pathway via increases in hepatic cGMP during fibrosis regression. Graphical abstract

Liver fibrosis affects over 100 million people in the world; it represents a multifactorial, fibro-inflammatory disorder characterized by exacerbated production of extracellular matrix with consequent aberration of hepatic tissue. The aetiology of this disease is very complex and seems to involve a broad spectrum of factors including the lifestyle, environment factors, genes and epigenetic changes. More evidences indicate that angiogenesis, a process consisting in the formation of new blood vessels from pre-existing vessels, plays a crucial role in the progression of liver fibrosis. Central to the pathogenesis of liver fibrosis is the hepatic stellate cells (HSCs) which represent a crossroad among inflammation, fibrosis and angiogenesis. Quiescent HSCs can be stimulated by a host of growth factors, pro-inflammatory mediators produced by damaged resident liver cell types, as well as by hypoxia, contributing to neoangiogenesis, which in turn can be a bridge between acute and chronic inflammation. As matter of fact, studies demonstrated that neutralization of vascular endothelial growth factor as well as other proangiogenic agents can attenuate the progression of liver fibrosis. With this review, our intent is to discuss the cause and the role of angiogenesis in liver fibrosis focusing on the current knowledge about the impact of anti-angiogenetic therapies in this pathology.

Aims Liver fibrosis predisposes patients to liver failure and hepatocellular carcinoma. Various markers, which can be calculated easily from serum parameters, have been reported to predict liver fibrosis accurately. This study investigated the prognostic factors, including blood‐based markers for liver fibrosis of patients with hepatocellular carcinoma following initial curative hepatectomy. Methods This retrospective study included 407 patients with hepatocellular carcinoma who underwent initial curative hepatectomy between April 2010 and December 2017. We investigated prognosis‐associated variables in these patients. Results Among the blood‐based markers for liver fibrosis examined in this study, the steatosis‐associated fibrosis estimator score demonstrated the best predictive capabilities. This score was revealed as a poor prognostic factor for both overall survival and recurrence‐free survival in patients with hepatocellular carcinoma following initial curative hepatectomy. A high steatosis‐associated fibrosis estimator score was independently associated with poor overall survival and recurrence‐free survival. After propensity score‐matching to minimize bias between high‐ and low‐steatosis‐associated fibrosis estimator score groups, the high steatosis‐associated fibrosis estimator score remained associated with poor overall survival and recurrence‐free survival. Conclusions The steatosis‐associated fibrosis estimator score is an independent predictor of long‐term prognosis in patients with hepatocellular carcinoma following initial curative hepatectomy. A high preoperative SAFE score was found to be independently associated with a poor prognosis in patients with HCC after initial curative hepatectomy. The preoperative SAFE score reflects the degree of liver fibrosis and is a useful assessment index for predicting the prognosis of patients who have undergone curative hepatectomy of HCC.

The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22α -RBPj mice (RBPj ), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl -induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.

Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.

This study investigates the relationship between Cyclin D1 (CCND1) gene and promoter methylation and liver fibrosis (LF)/liver cirrhosis (LC)induced by chronic hepatitis B (CHB). Peripheral blood mononuclear cells (PBMCs) are collected from patients diagnosed with chronic hepatitis B (CHB) and hepatitis B-related LF/LC, as well as from healthy individuals. The mRNA levels and promoter methylation of the CCND1 gene are measured. Single-cell analysis is performed to determine the cell types primarily expressing the CCND1 gene in LF/LC. The GSE84044 dataset is utilized to validate the experimental results. Single-gene GSEA and immune infiltration analyses are conducted to identify significant pathways and immune characteristics associated with the CCND1 gene. The mRNA level of CCND1 in PBMCs from patients with hepatitis B-related LF/LC is elevated compared to those with chronic hepatitis B (CHB) and healthy individuals, while the promoter methylation level of CCND1 is reduced. Single-cell analysis indicates high expression of CCND1 in M2 macrophages (M2) and T cells. The GSE84044 dataset confirms higher CCND1 mRNA levels in liver tissues from patients with CHB-related LF/LC compared to CHB patients. Single-gene GSEA analysis associates CCND1 expression with natural killer cell-mediated cytotoxicity, T cell receptor signaling, and B cell receptor signaling pathways. Increased expression of CCND1 enhances immune infiltration during the fibrosis/cirrhosis process of CHB. The CCND1 expression and promoter methylation may be involved in the process of LF/LC in CHB and may be related to the immune response in the course of the disease.

Excessive accumulation of extracellular matrix (ECM) components within the liver leads to a pathological condition known as liver fibrosis. Alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune issues, and viral hepatitis cause chronic liver injury. Exploring potential therapeutic targets and understanding the molecular mechanisms involved in liver fibrosis are essential for the development of effective interventions. The goal of this comprehensive review is to explain how the PI3K/AKT signaling pathway contributes to the reduction of liver fibrosis. The potential of this pathway as a therapeutic target is investigated through a summary of results from in vivo and in vitro studies. Studies focusing on PI3K/AKT activation have shown a significant decrease in fibrosis markers and a significant improvement in liver function. The review emphasizes how this pathway may prevent ECM synthesis and hepatic stellate cell (HSC) activation, ultimately reducing the fibrotic response. The specific mechanisms and downstream effectors of the PI3K/AKT pathway in liver fibrosis constitute a rapidly developing field of study. In conclusion, the PI3K/AKT signaling pathway plays a significant role in attenuating liver fibrosis. Its complex role in regulating HSC activation and ECM production, demonstrated both in vitro and in vivo , underscores its potential as a effective therapeutic approach for managing liver fibrosis and slowing disease progression. A comprehensive review of this field provides valuable insights into its future developments and implications for clinical applications.

Approximately 30% of the worldwide population has at least one risk factor for liver disease. Identifying advanced liver disease before the occurrence of complications remains a difficult challenge in clinical practice, where diagnosis comes too late for many patients, at the time of liver decompensation or palliative hepatocellular carcinoma, with poor short-term prognosis. Noninvasive, blood- or elastography-based tests of liver fibrosis (NITs) have been developed for the early diagnosis of advanced liver fibrosis. Recent population-based studies evaluating the screening of liver fibrosis with these NITs have provided important information on at-risk groups that should be targeted. New measures based on the sequential use of NITs help to better organize the referral of at-risk patients to the liver specialist. However, energizing these measures will require increased awareness of both chronic liver diseases and the use of NITs among non-specialists.