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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of liver fibrosis? ​

Abstract ​

Liver fibrosis is a pathological condition resulting from chronic liver injury, marked by excessive accumulation of extracellular matrix (ECM) components that disrupt liver architecture and function. The primary initiating factors include chronic liver diseases such as viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). This review elucidates the complex mechanisms of liver fibrosis, emphasizing the pivotal role of hepatic stellate cells (HSCs), inflammation, and ECM remodeling. Activated HSCs transition from a quiescent state to myofibroblast-like cells, producing ECM components, particularly collagen, in response to cytokines like TGF-β. Inflammation plays a crucial role, as pro-inflammatory cytokines recruit immune cells, perpetuating a cycle of injury and fibrosis. Signaling pathways, including TGF-β, Wnt/β-catenin, and Hedgehog, are integral to HSC activation and fibrogenesis. The composition of ECM in fibrosis, primarily collagen types I and III, is influenced by a dynamic balance between MMPs and TIMPs, which regulate ECM turnover. This review highlights the importance of understanding these mechanisms for developing effective therapeutic strategies to manage liver fibrosis, ultimately improving patient outcomes and addressing a significant global health burden.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Pathophysiology of Liver Fibrosis
    • 2.1 Initiating Factors of Liver Injury
    • 2.2 Cellular Responses to Liver Injury
  • 3 Role of Hepatic Stellate Cells in Fibrogenesis
    • 3.1 Activation of Hepatic Stellate Cells
    • 3.2 Mechanisms of ECM Production
  • 4 Contribution of Immune Cells
    • 4.1 Role of Macrophages
    • 4.2 Involvement of Lymphocytes
  • 5 Signaling Pathways in Liver Fibrosis
    • 5.1 TGF-β Signaling
    • 5.2 Other Key Pathways (e.g., Wnt/β-catenin, Hedgehog)
  • 6 Extracellular Matrix Remodeling
    • 6.1 Composition of ECM in Fibrosis
    • 6.2 Matrix Metalloproteinases and Tissue Inhibitors
  • 7 Summary

1 Introduction ​

Liver fibrosis is a complex pathological condition that arises as a result of chronic liver injury, characterized by the excessive accumulation of extracellular matrix (ECM) components, which leads to significant alterations in liver architecture and function. This progressive scarring process is commonly associated with various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD) [1][2]. As liver fibrosis can progress to cirrhosis and ultimately liver failure, understanding its underlying mechanisms is crucial for developing effective therapeutic strategies [3].

The significance of researching liver fibrosis cannot be overstated. It represents a major global health burden, with increasing prevalence due to the rise of lifestyle-related diseases such as obesity and diabetes [4]. Furthermore, the economic impact of liver diseases is profound, necessitating an urgent need for effective treatment options. Current therapeutic approaches remain limited, and the lack of specific antifibrotic drugs highlights the critical need for novel strategies targeting the fibrogenic process [5]. This review aims to elucidate the multifaceted mechanisms involved in liver fibrosis, which may pave the way for targeted therapies and improved patient outcomes.

Research into the mechanisms of liver fibrosis has evolved significantly over the past two decades. Initially, fibrosis was viewed as a passive scarring process; however, recent studies have demonstrated that it is a dynamic, bidirectional process involving various cellular and molecular players [2]. Key cell types implicated in the fibrogenic process include hepatic stellate cells (HSCs), hepatocytes, and various immune cells, each contributing to the complex interplay that drives fibrosis [3][6]. The activation of HSCs is particularly critical, as these cells transition from a quiescent state to an activated myofibroblast phenotype, leading to increased ECM production [1].

Moreover, the role of inflammatory responses and signaling pathways in liver fibrosis has garnered considerable attention. Cytokines such as transforming growth factor-beta (TGF-β) and various chemokines play pivotal roles in mediating HSC activation and ECM deposition [7]. Additionally, the intricate crosstalk between inflammatory mediators, signaling pathways, and ECM components creates a fibrotic niche that sustains the fibrogenic process [3]. Understanding these pathways is essential for identifying potential therapeutic targets.

This review is organized into several key sections to provide a comprehensive overview of the mechanisms of liver fibrosis. The first section will delve into the pathophysiology of liver fibrosis, focusing on the initiating factors of liver injury and the cellular responses that ensue. Following this, we will explore the role of hepatic stellate cells in fibrogenesis, detailing their activation and the mechanisms by which they produce ECM. The contribution of immune cells, particularly macrophages and lymphocytes, will be examined in the subsequent section, highlighting their roles in the fibrotic response.

Next, we will discuss the various signaling pathways implicated in liver fibrosis, with a focus on TGF-β signaling and other critical pathways such as Wnt/β-catenin and Hedgehog. The subsequent section will address ECM remodeling, detailing its composition in fibrosis and the roles of matrix metalloproteinases and tissue inhibitors. Finally, we will summarize the key findings and propose future directions for research aimed at unraveling the complexities of liver fibrosis.

In conclusion, a thorough understanding of the mechanisms underlying liver fibrosis is vital for the development of effective therapeutic interventions. This review aims to synthesize current knowledge in the field, identify gaps in research, and propose directions for future studies, ultimately contributing to improved management of liver fibrosis and its associated complications.

2 Pathophysiology of Liver Fibrosis ​

2.1 Initiating Factors of Liver Injury ​

Liver fibrosis is a complex pathological process characterized by the excessive accumulation of extracellular matrix (ECM) components in response to chronic liver injury. The primary initiating factors of liver injury leading to fibrosis include various forms of chronic liver diseases such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and autoimmune liver diseases. The progression of liver fibrosis involves several interrelated mechanisms, primarily centered around the activation of hepatic stellate cells (HSCs), inflammation, and ECM remodeling.

One of the key initiating factors of liver injury is the repetitive damage to hepatocytes, which triggers a cascade of inflammatory responses. Following hepatocyte injury, there is an activation of inflammatory pathways, leading to the recruitment of immune cells and the release of pro-inflammatory cytokines. This inflammatory response is crucial as it not only contributes to further hepatocyte damage but also activates HSCs, which are the primary fibrogenic cells in the liver. Upon activation, HSCs transdifferentiate into myofibroblast-like cells, which are responsible for the excessive production of ECM components, including collagen [2].

In addition to the direct injury to hepatocytes, various extracellular mechanisms such as apoptotic bodies, paracrine stimuli, oxidative stress, and persistent inflammation play significant roles in the activation of HSCs [1]. The interplay between these factors leads to a fibrotic microenvironment characterized by abnormal ECM deposition, scar formation, and angiogenesis, ultimately resulting in the architectural distortion of the liver [6].

Recent studies have highlighted the involvement of epigenetic and epitranscriptomic modifications in the pathogenesis of liver fibrosis. These modifications can regulate gene expression in HSCs and other liver cells, influencing their activation and the fibrogenic response [5]. For instance, the N6-methyladenosine (m6A) modification has been shown to interact with non-coding RNAs and DNA methylation processes, further complicating the regulatory landscape of fibrogenesis [6].

The crosstalk among various inflammatory mediators also plays a significant role in liver fibrosis. The activation of HSCs is mediated through a network of signaling pathways involving cytokines such as transforming growth factor-beta (TGF-β) and toll-like receptors, which promote fibrogenesis by enhancing the inflammatory response and stimulating ECM production [8]. This crosstalk results in a feedback loop where inflammation leads to more fibrosis, and increased fibrosis further perpetuates inflammation [6].

Moreover, metabolic reprogramming in HSCs has emerged as a critical aspect of liver fibrosis. Activated HSCs undergo metabolic changes that support their fibrogenic activity, including upregulation of glycolysis to meet the increased energy demands during their activation [9]. This metabolic shift is influenced by various factors, including glucose transport and the secretion of metabolic byproducts, which can further modulate the fibrotic response [10].

In summary, the mechanisms of liver fibrosis involve a multifaceted interplay of hepatocyte injury, inflammation, HSC activation, ECM remodeling, and metabolic reprogramming. Understanding these pathways is crucial for developing effective therapeutic strategies to prevent or reverse liver fibrosis and its progression to cirrhosis and liver failure.

2.2 Cellular Responses to Liver Injury ​

Liver fibrosis is a complex pathophysiological process characterized by the excessive accumulation of extracellular matrix (ECM) components, primarily due to chronic liver injury. This condition represents a wound-healing response to various forms of liver damage, including viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease. The activation of hepatic stellate cells (HSCs) plays a central role in the fibrogenic response, driven by multiple cellular and molecular mechanisms.

One of the primary mechanisms involves the activation and proliferation of HSCs, which are the main ECM-producing cells in the liver. Following liver injury, HSCs undergo a transformation into myofibroblast-like cells, which secrete collagen and other ECM proteins. This process is stimulated by various factors, including cytokines and growth factors released from damaged hepatocytes and infiltrating inflammatory cells. For instance, pro-inflammatory cytokines such as transforming growth factor-beta (TGF-β) are crucial in promoting HSC activation and proliferation, leading to increased ECM deposition [2].

The interplay between inflammation and fibrosis is another critical aspect of liver fibrosis pathogenesis. Damaged hepatocytes release pro-inflammatory mediators that recruit inflammatory cells to the site of injury, further amplifying the fibrogenic response. The crosstalk between these inflammatory mediators and HSCs creates a feedback loop that exacerbates liver damage and promotes fibrosis [8]. Moreover, the presence of oxidative stress, characterized by the accumulation of reactive oxygen species (ROS), has been implicated in HSC activation and ECM production. Oxidative stress can directly stimulate HSCs or induce hepatocyte injury, contributing to the fibrotic process [11].

Additionally, the microenvironment within the liver plays a significant role in the progression of fibrosis. The abnormal deposition of ECM components, combined with altered cellular interactions, can lead to the formation of a fibrotic niche that perpetuates HSC activation and fibrogenesis. Recent studies utilizing advanced techniques such as single-cell RNA sequencing have highlighted the heterogeneity of cells within the fibrotic liver and their dynamic interactions, which can influence the overall fibrotic response [3].

Epigenetic modifications are also emerging as crucial regulatory mechanisms in liver fibrosis. These modifications can alter gene expression patterns in HSCs and other liver cells, affecting their responses to injury and inflammation. For example, changes in DNA methylation and histone modifications have been linked to the activation of fibrogenic pathways [5]. Furthermore, non-coding RNAs, such as microRNAs, have been identified as important regulators of fibrogenesis, influencing HSC activation and ECM production [12].

In summary, the mechanisms underlying liver fibrosis are multifaceted and involve a combination of cellular responses to liver injury, including HSC activation, inflammatory cell recruitment, oxidative stress, and epigenetic regulation. Understanding these intricate pathways is essential for developing targeted therapeutic strategies aimed at preventing or reversing liver fibrosis.

3 Role of Hepatic Stellate Cells in Fibrogenesis ​

3.1 Activation of Hepatic Stellate Cells ​

Liver fibrosis is a complex pathological process characterized by the excessive accumulation of extracellular matrix (ECM), primarily driven by activated hepatic stellate cells (HSCs). The activation of HSCs is a pivotal event in the development of liver fibrosis, as these cells transition from a quiescent state to a proliferative, fibrogenic myofibroblast-like phenotype. This transformation is influenced by various factors, including chronic liver injury, inflammation, and metabolic stress.

In a healthy liver, HSCs are quiescent and store vitamin A, functioning primarily as pericytes. However, upon liver injury—regardless of the etiology—HSCs become activated. This activation can be triggered by multiple stimuli, including cytokines, oxidative stress, and changes in the extracellular matrix, which may originate from resident liver cells such as hepatocytes and Kupffer cells, as well as infiltrating leukocytes[13][14].

Once activated, HSCs undergo a series of phenotypic changes that enhance their fibrogenic capabilities. They proliferate, migrate, and synthesize large amounts of ECM components, particularly collagen type I, which is crucial for the formation of fibrous tissue. The activated HSCs also exhibit altered metabolism, favoring glycolysis and glutaminolysis, which supports their fibrogenic activities[15][16].

The crosstalk between HSCs and other cell types in the liver microenvironment significantly influences HSC activation. Interactions with hepatocytes, sinusoidal endothelial cells, and immune cells create a dynamic network that modulates the activation state of HSCs. For instance, signals from damaged hepatocytes and recruited immune cells can perpetuate inflammation and further activate HSCs, creating a vicious cycle that exacerbates fibrosis[17][18].

Moreover, the role of intracellular signaling pathways in HSC activation is critical. Factors such as platelet-derived growth factor (PDGF) and tumor necrosis factor-alpha (TNF-α) activate specific signaling cascades, including mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K), which contribute to the fibrogenic phenotype of HSCs[19][20].

The progression of liver fibrosis can ultimately lead to cirrhosis and hepatocellular carcinoma if left unchecked. However, emerging evidence suggests that liver fibrosis may be reversible, highlighting the importance of understanding the mechanisms underlying HSC activation and the potential for therapeutic interventions aimed at targeting these pathways[15][21].

In summary, the activation of hepatic stellate cells is central to the fibrogenic process in liver disease. Their transformation from quiescent cells to active myofibroblasts, influenced by a complex interplay of signals from the liver microenvironment, underpins the development and progression of liver fibrosis. Understanding these mechanisms is essential for developing effective therapeutic strategies to combat liver fibrosis and its associated complications.

3.2 Mechanisms of ECM Production ​

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins, primarily type I collagen, which results from a wound-healing response to chronic liver injury. The activation of hepatic stellate cells (HSCs) plays a pivotal role in this fibrogenic process. HSCs, when activated, undergo a transformation from quiescent vitamin A-rich cells into proliferative, fibrogenic, and contractile myofibroblasts. This activation is crucial as HSCs are the primary source of ECM in liver fibrosis [22].

The fibrogenic response involves several mechanisms. Firstly, activated HSCs directly synthesize ECM proteins. They respond to various profibrotic cytokines, such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), which play significant roles in mediating the fibrogenic response. These cytokines activate signaling pathways including mitogen-activated protein kinase (MAPK) signaling, specifically involving p38 MAPK, and focal adhesion kinase-phosphatidylinositol 3-kinase-Akt-p70 S6 kinase (FAK-PI3K-Akt-p70(S6K)) pathways. These pathways are crucial for regulating cell proliferation and collagen gene expression [23].

TGF-beta, in particular, is a key cytokine in the fibrogenesis process. It activates the Smad signaling pathway, which is known to influence collagen gene expression. Research has shown that Smad and p38 MAPK signaling can independently and additively regulate the expression of the alpha1(I) collagen gene, with p38 MAPK also increasing the stability of alpha1(I) collagen mRNA, thereby enhancing collagen synthesis and deposition [23].

Moreover, the interaction between HSCs and other liver cells, such as hepatocytes and immune cells, contributes to the complexity of liver fibrogenesis. Hepatocytes, traditionally viewed as passive victims in liver injury, are now recognized as active participants that can influence HSC activation and ECM production through signaling pathways [24]. This indicates a more intricate network of cellular interactions and signaling mechanisms in the fibrogenic process.

In summary, the mechanisms of liver fibrosis primarily involve the activation of HSCs, which are central to ECM production. This process is regulated by various cytokines and signaling pathways, particularly TGF-beta and MAPK pathways, which orchestrate the fibrogenic response through both direct ECM synthesis and the modulation of cellular interactions within the liver [21]. Understanding these mechanisms is crucial for developing targeted therapies aimed at mitigating liver fibrosis and its progression to cirrhosis and liver failure [25].

4 Contribution of Immune Cells ​

4.1 Role of Macrophages ​

Liver fibrosis is a chronic pathological condition characterized by excessive deposition of extracellular matrix (ECM) and the continuous loss of liver function due to various etiological factors, including chronic inflammation and injury. The role of immune cells, particularly macrophages, is critical in the mechanisms underlying liver fibrosis.

Macrophages, as the most abundant immune cells in the liver, are key drivers in the fibrotic process. They exhibit significant heterogeneity and can be classified into different subpopulations, primarily M1 and M2 macrophages. M1 macrophages are typically pro-inflammatory, promoting fibrosis through the secretion of various cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (ILs), while M2 macrophages are generally anti-inflammatory and reparative, contributing to tissue repair and fibrosis resolution[26].

The activation and polarization of macrophages in the liver are influenced by their microenvironment, which includes interactions with other cell types such as hepatic stellate cells (HSCs) and hepatocytes. HSCs are critical mediators of fibrogenesis, and their activation is significantly modulated by macrophages. For instance, macrophages can secrete pro-fibrotic cytokines like transforming growth factor-beta (TGF-β) and Galectin-3, which further stimulate HSC activation and promote ECM deposition[26].

Moreover, macrophages can engage in crosstalk with HSCs through various signaling pathways. This interaction is crucial for the progression of liver fibrosis, as activated HSCs can enhance macrophage recruitment and activation, creating a feedback loop that exacerbates the fibrotic response[27]. During the resolution phase of fibrosis, M2 macrophages may secrete matrix metalloproteinases (MMPs) that degrade ECM components, thus facilitating tissue remodeling and fibrosis regression[26].

In addition to their roles in promoting fibrosis, macrophages also participate in the resolution of liver injury. They can phagocytose apoptotic cells and debris, which is essential for restoring tissue homeostasis[28]. The balance between pro-fibrotic and anti-fibrotic macrophage functions is vital for determining the outcome of liver fibrosis. Dysregulation of this balance can lead to either progressive fibrosis or effective resolution[29].

Emerging therapeutic strategies targeting macrophages aim to modulate their activity to promote fibrosis resolution. These include the use of agents that inhibit macrophage recruitment, alter macrophage polarization towards the M2 phenotype, or enhance their phagocytic activity[30]. Understanding the intricate roles of macrophages in liver fibrosis can provide valuable insights for developing effective treatments for this condition.

4.2 Involvement of Lymphocytes ​

Liver fibrosis is a complex pathological process characterized by excessive accumulation of extracellular matrix (ECM) components due to chronic liver injury, and it involves a multifaceted interplay between various immune cells, particularly lymphocytes. The mechanisms underlying liver fibrosis can be dissected into several key components, with a significant focus on the contribution of immune cells, especially lymphocytes.

The activation of hepatic stellate cells (HSCs) plays a central role in the development of liver fibrosis. These cells, when activated, become the primary source of ECM in the liver. Immune cells, particularly T lymphocytes, are critical regulators of HSC activation and, consequently, liver fibrosis progression. T cells, including CD4+ helper T cells and CD8+ cytotoxic T cells, secrete various cytokines and chemokines that modulate inflammation and influence the behavior of HSCs. For instance, the ratio of CD8+ T cells to CD4+ T cells is significantly higher in the liver compared to peripheral blood, indicating a localized immune response that can exacerbate fibrogenesis through the secretion of pro-inflammatory cytokines [31].

Moreover, regulatory T cells (Tregs) and T helper 17 (Th17) cells have been shown to exhibit opposing roles in liver fibrosis. While Th17 cells promote inflammation and contribute to fibrogenesis, Tregs generally exert protective effects by regulating immune responses and potentially attenuating HSC activation [32]. The dichotomy of these immune subsets underscores the complexity of the immune response in liver fibrosis, where both pro-fibrotic and anti-fibrotic activities are present.

Dendritic cells (DCs) also play a pivotal role in mediating the crosstalk between T lymphocytes and HSCs. They act as professional antigen-presenting cells, influencing T cell differentiation and function. The interaction between DCs and T cells is crucial for maintaining immune homeostasis in the liver, and any disruption in this crosstalk can lead to an imbalance that favors fibrogenesis [33]. Furthermore, the production of specific cytokines by T cells can further regulate the function of DCs, creating a feedback loop that can either promote or inhibit fibrosis [34].

The involvement of natural killer (NK) cells is also noteworthy in the context of liver fibrosis. NK cells can exert protective effects by directly killing activated HSCs, thereby limiting fibrogenesis. Their cytotoxic activity is mediated through mechanisms such as the NKG2D pathway, which targets activated HSCs for destruction [35]. However, the balance between the pro-fibrotic effects of activated T cells and the protective role of NK cells is crucial for determining the overall outcome of liver fibrosis [36].

In summary, the mechanisms of liver fibrosis involve a dynamic interplay of immune cells, particularly lymphocytes, which can both promote and inhibit fibrogenesis. T lymphocytes, through their diverse subsets, orchestrate the inflammatory response and influence HSC activation. Dendritic cells mediate interactions between T cells and HSCs, while NK cells provide a counterbalance to HSC activation. Understanding these mechanisms is essential for developing targeted therapeutic strategies to manage liver fibrosis effectively.

5 Signaling Pathways in Liver Fibrosis ​

5.1 TGF-β Signaling ​

Liver fibrosis is a complex pathological process characterized by excessive accumulation of extracellular matrix components, primarily collagens, resulting from various chronic liver injuries. One of the key players in the progression of liver fibrosis is the Transforming Growth Factor-beta (TGF-β) signaling pathway, which plays a multifaceted role in regulating cellular processes involved in fibrogenesis.

TGF-β is a master profibrogenic cytokine that significantly influences the activation of hepatic stellate cells (HSCs), which are pivotal in the production of extracellular matrix (ECM) proteins. The activation of HSCs involves their transdifferentiation into myofibroblasts, which are the primary source of collagen and other ECM components. This process is often triggered by chronic liver injury, leading to the release of TGF-β from various cell types, including macrophages and damaged hepatocytes, which subsequently activates HSCs through the canonical Smad-dependent signaling pathway as well as non-Smad pathways [37][38].

The TGF-β signaling pathway initiates when TGF-β binds to its receptors, leading to the phosphorylation of Smad proteins, particularly Smad2 and Smad3. These phosphorylated Smads then form complexes with Smad4, translocate to the nucleus, and regulate the transcription of genes involved in fibrosis, including those encoding collagen and other ECM components [37][39]. Importantly, TGF-β also induces epithelial-mesenchymal transition (EMT) in hepatocytes, which contributes to the pool of activated myofibroblasts and exacerbates fibrosis [39].

Moreover, TGF-β signaling is involved in the modulation of inflammation, which is another critical aspect of liver fibrosis. The pathway can enhance the production of pro-inflammatory cytokines and recruit immune cells, further promoting the fibrogenic environment [40]. Recent studies have highlighted the role of TGF-β in activating the NLRP3 inflammasome in HSCs, linking it to the amplification of liver inflammation and fibrosis [40].

In addition to the canonical Smad pathway, TGF-β also engages various non-Smad signaling pathways, including the TAK1-NF-kB and MAPK pathways, which contribute to its profibrogenic effects [37][41]. These pathways facilitate not only the activation of HSCs but also the regulation of ECM remodeling and inflammatory responses, underscoring the pleiotropic nature of TGF-β signaling in liver disease.

In summary, the mechanisms underlying liver fibrosis involve a complex interplay of TGF-β signaling pathways that regulate HSC activation, ECM production, inflammation, and cell plasticity. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to mitigate liver fibrosis and its progression to cirrhosis and hepatocellular carcinoma. Targeting TGF-β and its associated signaling pathways has emerged as a promising approach in the treatment of liver fibrosis, with ongoing research focusing on the development of specific inhibitors and novel therapeutic modalities [41][42].

5.2 Other Key Pathways (e.g., Wnt/β-catenin, Hedgehog) ​

Liver fibrosis is a progressive condition characterized by the excessive accumulation of extracellular matrix components, primarily collagen, resulting from chronic liver injury. The pathogenesis of liver fibrosis involves complex interactions among various signaling pathways, with the Wnt/β-catenin and Hedgehog pathways playing crucial roles.

The Wnt/β-catenin signaling pathway is significant in liver fibrosis development. In a healthy liver, the canonical Wnt pathway is typically inactive; however, it becomes activated in response to liver injuries. This activation leads to the proliferation and activation of hepatic stellate cells (HSCs), which are pivotal in the fibrogenesis process. The activation of the β-catenin Wnt pathway inhibits hepatocyte regeneration by promoting the deposition of extracellular matrix (ECM) and the formation of scar tissue. This dysregulation results in reduced liver function as advanced fibrosis progresses [43].

Research indicates that selective inhibition of β-catenin can mitigate inflammatory processes associated with Wnt activation, reduce the growth of activated HSCs, and decrease collagen synthesis and angiogenesis. Consequently, these actions help in attenuating the progression of liver fibrosis in vivo. Therapeutic strategies targeting the Wnt pathway involve blocking components such as frizzled receptors, low-density lipoprotein receptor-related protein 5/6, glycogen synthase kinase-3 beta (GSK-3β), and cyclic-AMP response element-binding protein (CBP) [43].

The Hedgehog (Hh) signaling pathway also plays a critical role in liver fibrosis. It regulates various cellular processes, including cell proliferation, activation, and differentiation of HSCs. In the context of liver injury, Hh signaling becomes reactivated and contributes to fibrogenesis and the activation of HSCs. The pathway's modulation of HSC fate is influenced by several factors, including DNA methylation and microRNA activity [44]. The interplay between Hh and Wnt pathways has been observed, indicating that β-catenin can enhance the transcriptional activity of Hedgehog target genes, thereby influencing fibrogenesis [45].

In summary, the mechanisms underlying liver fibrosis are significantly influenced by the Wnt/β-catenin and Hedgehog signaling pathways. The activation of these pathways promotes the proliferation and activation of HSCs, leading to increased ECM production and reduced liver function. Targeting these pathways offers promising therapeutic avenues for managing liver fibrosis and improving liver health.

6 Extracellular Matrix Remodeling ​

6.1 Composition of ECM in Fibrosis ​

Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) components, which plays a critical role in the pathogenesis of the disease. The ECM in liver fibrosis consists primarily of collagen types I and III, along with various non-collagenous proteins that contribute to the structural integrity and functional properties of the liver. The composition and remodeling of the ECM are influenced by multiple cellular and molecular mechanisms.

The activation of hepatic stellate cells (HSCs) is a key event in the development of liver fibrosis. These cells, which are the primary fibrogenic cells in the liver, undergo a transformation into myofibroblast-like cells in response to chronic liver injury. This activation leads to an increase in the synthesis of ECM proteins, particularly fibrillar collagens, which accumulate in response to ongoing liver damage [46].

The remodeling of the ECM is a dynamic process involving both the deposition and degradation of matrix components. Matrix metalloproteinases (MMPs) play a crucial role in ECM degradation, as they are responsible for the breakdown of collagen and other ECM proteins. The activity of MMPs is regulated by tissue inhibitors of metalloproteinases (TIMPs), creating a balance between ECM synthesis and degradation [47]. In liver fibrosis, this balance is often disrupted, leading to an excess of ECM deposition and impaired remodeling [48].

Recent studies have highlighted the heterogeneity of ECM components in fibrotic liver tissue. For instance, different collagen types exhibit distinct roles and regulatory mechanisms during fibrogenesis. The composition of the ECM can vary depending on the etiology of liver injury, with specific changes observed in the levels of collagen cross-linking and stiffness, which further influence the behavior of HSCs and other liver cells [49].

Additionally, the interplay between various cell types, including immune cells, endothelial cells, and mesenchymal cells, contributes to the ECM remodeling process. For example, cytokines and growth factors released by activated immune cells can promote the activation of HSCs and enhance ECM production [14]. The ECM itself serves as a signaling platform that modulates cellular responses, influencing processes such as cell migration, proliferation, and differentiation [3].

The mechanical properties of the ECM, such as stiffness, also play a significant role in liver fibrosis. Increased matrix stiffness can activate signaling pathways that further drive the fibrogenic response, creating a feedback loop that exacerbates fibrosis [49]. Understanding these mechanisms provides insights into potential therapeutic strategies aimed at reversing or preventing liver fibrosis by targeting specific pathways involved in ECM remodeling [46][50].

In summary, the composition and remodeling of the ECM in liver fibrosis are regulated by a complex interplay of cellular activation, protein synthesis and degradation, and mechanical signaling. This intricate network of interactions underlies the pathological changes observed in fibrotic liver tissue and highlights potential targets for therapeutic intervention.

6.2 Matrix Metalloproteinases and Tissue Inhibitors ​

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, primarily collagen, due to a dysregulated balance between matrix synthesis and degradation. This pathological process involves various cellular and molecular mechanisms, particularly focusing on the roles of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs).

Matrix metalloproteinases are a family of zinc-dependent endopeptidases responsible for the degradation of ECM components. They play a crucial role in both fibrogenesis and fibrolysis, contributing to the dynamic remodeling of the liver's architecture. The balance between MMPs and TIMPs is vital in maintaining ECM homeostasis. MMPs are classified into different groups based on their substrate specificity, including collagenases, gelatinases, and stromelysins, which target various ECM proteins such as collagens, laminins, and proteoglycans [47].

In the context of liver fibrosis, activated hepatic stellate cells (HSCs) are the primary source of ECM components and MMPs. These cells undergo a phenotypic transformation into myofibroblast-like cells in response to chronic liver injury, leading to increased synthesis of ECM proteins. However, the ability of HSCs to produce MMPs is also critical for ECM degradation. Studies have shown that the expression of MMPs, particularly MMP-2 and MMP-9, is upregulated in fibrotic conditions, facilitating the breakdown of excess collagen and contributing to the resolution of fibrosis [51].

Tissue inhibitors of metalloproteinases, on the other hand, regulate the activity of MMPs, preventing excessive degradation of the ECM. In liver fibrosis, an imbalance often occurs, with increased levels of TIMPs, particularly TIMP-1, leading to reduced MMP activity and consequently promoting ECM accumulation [52]. This imbalance between MMPs and TIMPs is a hallmark of fibrotic progression, as elevated TIMP levels can hinder the normal turnover of collagen and other ECM components, exacerbating the fibrotic response [53].

Moreover, mechanical cues from the ECM, such as stiffness, significantly influence the behavior of HSCs and the expression of MMPs and TIMPs. The interaction between matrix stiffness and plasma membrane tension modulates the secretion of TIMP-1 through pathways involving β1 integrin and RhoA, leading to altered ECM remodeling dynamics [54]. This mechanotransduction underscores the complexity of liver fibrosis, where both biochemical and mechanical signals converge to regulate the fibrotic process.

In summary, the mechanisms underlying liver fibrosis involve a delicate interplay between the synthesis and degradation of ECM components, primarily mediated by MMPs and TIMPs. The dysregulation of these enzymes leads to excessive ECM deposition, driving the progression of liver fibrosis. Understanding these mechanisms is crucial for developing targeted therapeutic strategies aimed at restoring the balance between MMPs and TIMPs to alleviate fibrosis [55][56].

7 Conclusion ​

The study of liver fibrosis has revealed a complex interplay of cellular and molecular mechanisms that contribute to its pathogenesis. Key findings indicate that hepatic stellate cells (HSCs) are central to the fibrogenic process, undergoing activation in response to chronic liver injury and contributing to excessive extracellular matrix (ECM) production. Inflammatory responses and the recruitment of immune cells, particularly macrophages and lymphocytes, play significant roles in exacerbating fibrosis. The activation of various signaling pathways, notably TGF-β, Wnt/β-catenin, and Hedgehog, underscores the multifaceted nature of fibrogenesis. Furthermore, the balance between ECM synthesis and degradation, mediated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), is crucial in determining the progression of liver fibrosis. Future research should focus on elucidating the specific roles of immune cell subsets and the impact of metabolic reprogramming in HSCs, as well as the potential for targeting these pathways therapeutically. Understanding these intricate mechanisms will pave the way for the development of novel antifibrotic therapies aimed at reversing or halting the progression of liver fibrosis and its complications, such as cirrhosis and hepatocellular carcinoma.

References ​

  • [1] Chengu Niu;Jing Zhang;Patrick I Okolo. The possible pathogenesis of liver fibrosis: therapeutic potential of natural polyphenols.. Pharmacological reports : PR(IF=3.8). 2024. PMID:39162986. DOI: 10.1007/s43440-024-00638-w.
  • [2] Rong-Jane Chen;Hsiang-Hua Wu;Ying-Jan Wang. Strategies to prevent and reverse liver fibrosis in humans and laboratory animals.. Archives of toxicology(IF=6.9). 2015. PMID:25963329. DOI: 10.1007/s00204-015-1525-6.
  • [3] Michitaka Matsuda;Ekihiro Seki. The liver fibrosis niche: Novel insights into the interplay between fibrosis-composing mesenchymal cells, immune cells, endothelial cells, and extracellular matrix.. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association(IF=3.5). 2020. PMID:32640349. DOI: 10.1016/j.fct.2020.111556.
  • [4] Guozhu Zhang;Kejia Wu;Xiaobo Jiang;Yuan Gao;Dong Ding;Hao Wang;Chongyuan Yu;Xiaozhong Wang;Naixin Jia;Li Zhu. The role of ferroptosis-related non-coding RNA in liver fibrosis.. Frontiers in cell and developmental biology(IF=4.3). 2024. PMID:39717848. DOI: 10.3389/fcell.2024.1517401.
  • [5] Runping Liu;Yajing Li;Qi Zheng;Mingning Ding;Huiping Zhou;Xiaojiaoyang Li. Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead.. Acta pharmaceutica Sinica. B(IF=14.6). 2024. PMID:38486982. DOI: 10.1016/j.apsb.2023.10.023.
  • [6] Qi-Qi Dong;Yang Yang;Hui Tao;Chao Lu;Jing-Jing Yang. m6A epitranscriptomic and epigenetic crosstalk in liver fibrosis: Special emphasis on DNA methylation and non-coding RNAs.. Cellular signalling(IF=3.7). 2024. PMID:39025344. DOI: 10.1016/j.cellsig.2024.111302.
  • [7] Shaoxi Diao;Liangyun Li;Jintong Zhang;Minglu Ji;Lijiao Sun;Wenwen Shen;Shuai Wu;Zixiang Chen;Cheng Huang;Jun Li. Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway.. Biochemical pharmacology(IF=5.6). 2025. PMID:40122149. DOI: 10.1016/j.bcp.2025.116884.
  • [8] Han-Jing Zhangdi;Si-Biao Su;Fei Wang;Zi-Yu Liang;Yu-Dong Yan;Shan-Yu Qin;Hai-Xing Jiang. Crosstalk network among multiple inflammatory mediators in liver fibrosis.. World journal of gastroenterology(IF=5.4). 2019. PMID:31543677. DOI: 10.3748/wjg.v25.i33.4835.
  • [9] M Eugenia Delgado;Beatriz I Cárdenas;Núria Farran;Mercedes Fernandez. Metabolic Reprogramming of Liver Fibrosis.. Cells(IF=5.2). 2021. PMID:34944111. DOI: 10.3390/cells10123604.
  • [10] Xinhua Guo;Bowen Zheng;Jiahui Wang;Tiejian Zhao;Yang Zheng. Exploring the mechanism of action of Chinese medicine in regulating liver fibrosis based on the alteration of glucose metabolic pathways.. Phytotherapy research : PTR(IF=6.3). 2024. PMID:36433866. DOI: 10.1002/ptr.7667.
  • [11] G Svegliati Baroni;L D'Ambrosio;G Ferretti;A Casini;A Di Sario;R Salzano;F Ridolfi;S Saccomanno;A M Jezequel;A Benedetti. Fibrogenic effect of oxidative stress on rat hepatic stellate cells.. Hepatology (Baltimore, Md.)(IF=15.8). 1998. PMID:9500700. DOI: 10.1002/hep.510270313.
  • [12] R Brea;O Motiño;D Francés;C García-Monzón;J Vargas;M Fernández-Velasco;L Boscá;M Casado;P Martín-Sanz;N Agra. PGE2 induces apoptosis of hepatic stellate cells and attenuates liver fibrosis in mice by downregulating miR-23a-5p and miR-28a-5p.. Biochimica et biophysica acta. Molecular basis of disease(IF=4.2). 2018. PMID:29109031. DOI: 10.1016/j.bbadis.2017.11.001.
  • [13] J J Maher. Leukocytes as modulators of stellate cell activation.. Alcoholism, clinical and experimental research(IF=3.2). 1999. PMID:10371414. DOI: .
  • [14] Pierre Bedossa;Valérie Paradis. Liver extracellular matrix in health and disease.. The Journal of pathology(IF=5.2). 2003. PMID:12845618. DOI: 10.1002/path.1397.
  • [15] Tatiana Kisseleva;Souradipta Ganguly;Rabi Murad;Allen Wang;David A Brenner. Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis.. Gastroenterology(IF=25.1). 2025. PMID:40120772. DOI: 10.1053/j.gastro.2025.03.010.
  • [16] M Vera;N Nieto. Hepatic stellate cells and alcoholic liver disease.. Revista espanola de enfermedades digestivas(IF=4.0). 2006. PMID:17092199. DOI: 10.4321/s1130-01082006000900005.
  • [17] Fangming Yang;Heng Li;Yanmin Li;Yaokun Hao;Chenxiao Wang;Pan Jia;Xinju Chen;Suping Ma;Zhun Xiao. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis.. International immunopharmacology(IF=4.7). 2021. PMID:34426110. DOI: 10.1016/j.intimp.2021.108051.
  • [18] Luping Wang;Yi Huang;Jingrong Chen;Jialu Gao;Sihan Chen;Mingqi Zhao;Jiguo Lin;Shunqing Zhou;Yannan Shen;Yunyun Cheng. Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis.. Frontiers in cell and developmental biology(IF=4.3). 2025. PMID:40761743. DOI: 10.3389/fcell.2025.1635763.
  • [19] R S Britton;B R Bacon. Intracellular signaling pathways in stellate cell activation.. Alcoholism, clinical and experimental research(IF=3.2). 1999. PMID:10371415. DOI: .
  • [20] Takuma Tsuchida;Scott L Friedman. Mechanisms of hepatic stellate cell activation.. Nature reviews. Gastroenterology & hepatology(IF=51.0). 2017. PMID:28487545. DOI: 10.1038/nrgastro.2017.38.
  • [21] Scott L Friedman. Mechanisms of hepatic fibrogenesis.. Gastroenterology(IF=25.1). 2008. PMID:18471545. DOI: 10.1053/j.gastro.2008.03.003.
  • [22] D Li;S L Friedman. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.. Journal of gastroenterology and hepatology(IF=3.4). 1999. PMID:10440206. DOI: 10.1046/j.1440-1746.1999.01928.x.
  • [23] Christopher J Parsons;Motoki Takashima;Richard A Rippe. Molecular mechanisms of hepatic fibrogenesis.. Journal of gastroenterology and hepatology(IF=3.4). 2007. PMID:17567474. DOI: 10.1111/j.1440-1746.2006.04659.x.
  • [24] Thomas Tu;Sarah R Calabro;Aimei Lee;Annette E Maczurek;Magdalena A Budzinska;Fiona J Warner;Susan V McLennan;Nicholas A Shackel. Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?. Journal of gastroenterology and hepatology(IF=3.4). 2015. PMID:26239824. DOI: 10.1111/jgh.13065.
  • [25] Virginia Hernandez-Gea;Scott L Friedman. Pathogenesis of liver fibrosis.. Annual review of pathology(IF=34.5). 2011. PMID:21073339. DOI: 10.1146/annurev-pathol-011110-130246.
  • [26] Zhi Wang;Kailei Du;Nake Jin;Biao Tang;Wenwu Zhang. Macrophage in liver Fibrosis: Identities and mechanisms.. International immunopharmacology(IF=4.7). 2023. PMID:37224653. DOI: 10.1016/j.intimp.2023.110357.
  • [27] Yanbo Li;Zhengmin Cao;Yanping Lu;Chao Lei;Wenliang Lyu. Knowledge landscape of macrophage research in liver fibrosis: a bibliometric review of the literature from WoSCC.. Frontiers in pharmacology(IF=4.8). 2025. PMID:40406489. DOI: 10.3389/fphar.2025.1571879.
  • [28] Wahyu Widowati;Adilah Hafizha Nur Sabrina;Annisa Firdaus Sutendi;Fadhilah Haifa Zahiroh;Teresa Liliana Wargasetia;Ita Margaretha Nainggolan;Elham Rismani;Massoud Vosough. M2 Macrophages-Based Immunotherapy: A New Therapeutic Approach in Liver Fibrosis.. Advanced pharmaceutical bulletin(IF=4.1). 2025. PMID:40922738. DOI: 10.34172/apb.025.43855.
  • [29] Jinqiu Ran;Shengxia Yin;Rahma Issa;Qianwen Zhao;Guangqi Zhu;Huan Zhang;Qun Zhang;Chao Wu;Jie Li. Key role of macrophages in the progression of hepatic fibrosis.. Hepatology communications(IF=4.6). 2025. PMID:39670853. DOI: 10.1097/HC9.0000000000000602.
  • [30] Jialu Zhang;Zhaojing Xie;Xueyu Zhu;Chenxi Xu;Jiguo Lin;Mingqi Zhao;Yunyun Cheng. New insights into therapeutic strategies for targeting hepatic macrophages to alleviate liver fibrosis.. International immunopharmacology(IF=4.7). 2025. PMID:40378438. DOI: 10.1016/j.intimp.2025.114864.
  • [31] Hao Li;Peng Ding;Bo Peng;Ying-Zi Ming. Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis.. Hepatobiliary & pancreatic diseases international : HBPD INT(IF=4.4). 2021. PMID:33972160. DOI: 10.1016/j.hbpd.2021.04.007.
  • [32] Minjie Wan;Jiawen Han;Lili Ding;Feng Hu;Pujun Gao. Novel Immune Subsets and Related Cytokines: Emerging Players in the Progression of Liver Fibrosis.. Frontiers in medicine(IF=3.0). 2021. PMID:33869241. DOI: 10.3389/fmed.2021.604894.
  • [33] Isabella Lurje;Linda Hammerich;Frank Tacke. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer.. International journal of molecular sciences(IF=4.9). 2020. PMID:33036244. DOI: 10.3390/ijms21197378.
  • [34] Bingyu Wang;Liuxin Yang;Xingxing Yuan;Yang Zhang. Roles and therapeutic targeting of dendritic cells in liver fibrosis.. Journal of drug targeting(IF=3.9). 2024. PMID:38682473. DOI: 10.1080/1061186X.2024.2347365.
  • [35] Svetlana Radaeva;Rui Sun;Barbara Jaruga;Van T Nguyen;Zhigang Tian;Bin Gao. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.. Gastroenterology(IF=25.1). 2006. PMID:16472598. DOI: 10.1053/j.gastro.2005.10.055.
  • [36] Won-Il Jeong;Bin Gao. Innate immunity and alcoholic liver fibrosis.. Journal of gastroenterology and hepatology(IF=3.4). 2008. PMID:18336653. DOI: 10.1111/j.1440-1746.2007.05274.x.
  • [37] Isabel Fabregat;Joaquim Moreno-Càceres;Aránzazu Sánchez;Steven Dooley;Bedair Dewidar;Gianluigi Giannelli;Peter Ten Dijke; . TGF-β signalling and liver disease.. The FEBS journal(IF=4.2). 2016. PMID:26807763. DOI: 10.1111/febs.13665.
  • [38] Sen Zhang;Wu-Yi Sun;Jing-Jing Wu;Wei Wei. TGF-β signaling pathway as a pharmacological target in liver diseases.. Pharmacological research(IF=10.5). 2014. PMID:24844437. DOI: .
  • [39] Isabel Fabregat;Daniel Caballero-Díaz. Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis.. Frontiers in oncology(IF=3.3). 2018. PMID:30250825. DOI: 10.3389/fonc.2018.00357.
  • [40] Hwansu Kang;Eunhui Seo;Yoon Sin Oh;Hee-Sook Jun. TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells.. Molecular and cellular biochemistry(IF=3.7). 2022. PMID:35138513. DOI: 10.1007/s11010-022-04369-5.
  • [41] Weili Wang;Yilin Gao;Yizhen Chen;Meng Cheng;Yonghao Sang;Liuting Wei;Rong Dai;Yiping Wang;Lei Zhang. TGF-β inhibitors: the future for prevention and treatment of liver fibrosis?. Frontiers in immunology(IF=5.9). 2025. PMID:40655154. DOI: 10.3389/fimmu.2025.1583616.
  • [42] Wanchun Zhu;Yu Cui;Jiahao Qiu;Xin Zhang;Yueqiu Gao;Zhi Shang;Lingying Huang. Exploring the Therapeutic Potential of TGF-β Inhibitors for Liver Fibrosis: Targeting Multiple Signaling Pathways.. Journal of clinical and translational hepatology(IF=4.2). 2025. PMID:40937077. DOI: 10.14218/JCTH.2025.00029.
  • [43] Kristina Duspara;Kristina Bojanic;Josipa Ivanusic Pejic;Lucija Kuna;Tea Omanovic Kolaric;Vjera Nincevic;Robert Smolic;Aleksandar Vcev;Marija Glasnovic;Ines Bilic Curcic;Martina Smolic. Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update.. Journal of clinical and translational hepatology(IF=4.2). 2021. PMID:34966659. DOI: 10.14218/JCTH.2021.00065.
  • [44] Jing-Jing Yang;Hui Tao;Jun Li. Hedgehog signaling pathway as key player in liver fibrosis: new insights and perspectives.. Expert opinion on therapeutic targets(IF=4.4). 2014. PMID:24935558. DOI: 10.1517/14728222.2014.927443.
  • [45] Osamu Maeda;Masashi Kondo;Takayoshi Fujita;Noriyasu Usami;Takayuki Fukui;Kaoru Shimokata;Takafumi Ando;Hidemi Goto;Yoshitaka Sekido. Enhancement of GLI1-transcriptional activity by beta-catenin in human cancer cells.. Oncology reports(IF=3.9). 2006. PMID:16786128. DOI: .
  • [46] M Pinzani;K Rombouts. Liver fibrosis: from the bench to clinical targets.. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver(IF=3.8). 2004. PMID:15115333. DOI: 10.1016/j.dld.2004.01.003.
  • [47] M J Arthur. Degradation of matrix proteins in liver fibrosis.. Pathology, research and practice(IF=3.2). 1994. PMID:7899131. DOI: 10.1016/S0344-0338(11)80985-4.
  • [48] Elena Arriazu;Marina Ruiz de Galarreta;Francisco Javier Cubero;Marta Varela-Rey;María Pilar Pérez de Obanos;Tung Ming Leung;Aritz Lopategi;Aitor Benedicto;Ioana Abraham-Enachescu;Natalia Nieto. Extracellular matrix and liver disease.. Antioxidants & redox signaling(IF=6.1). 2014. PMID:24219114. DOI: 10.1089/ars.2013.5697.
  • [49] Guobao Chen;Bin Xia;Qiang Fu;Xiang Huang;Fuping Wang;Zhongmin Chen;Yonggang Lv. Matrix Mechanics as Regulatory Factors and Therapeutic Targets in Hepatic Fibrosis.. International journal of biological sciences(IF=10.0). 2019. PMID:31754325. DOI: 10.7150/ijbs.37500.
  • [50] Ursula E Lee;Scott L Friedman. Mechanisms of hepatic fibrogenesis.. Best practice & research. Clinical gastroenterology(IF=4.0). 2011. PMID:21497738. DOI: 10.1016/j.bpg.2011.02.005.
  • [51] Elke Roeb. Matrix metalloproteinases and liver fibrosis (translational aspects).. Matrix biology : journal of the International Society for Matrix Biology(IF=4.8). 2018. PMID:29289644. DOI: 10.1016/j.matbio.2017.12.012.
  • [52] Stefanie Hemmann;Jürgen Graf;Martin Roderfeld;Elke Roeb. Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies.. Journal of hepatology(IF=33.0). 2007. PMID:17383048. DOI: 10.1016/j.jhep.2007.02.003.
  • [53] Liang Shan;Fengling Wang;Dandan Zhai;Xiangyun Meng;Jianjun Liu;Xiongwen Lv. Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(IF=7.5). 2023. PMID:37002573. DOI: 10.1016/j.biopha.2023.114472.
  • [54] Dariusz Lachowski;Carlos Matellan;Sahana Gopal;Ernesto Cortes;Benjamin K Robinson;Alberto Saiani;Aline F Miller;Molly M Stevens;Armando E Del Río Hernández. Substrate Stiffness-Driven Membrane Tension Modulates Vesicular Trafficking via Caveolin-1.. ACS nano(IF=16.0). 2022. PMID:35255206. DOI: 10.1021/acsnano.1c10534.
  • [55] Martin Roderfeld. Matrix metalloproteinase functions in hepatic injury and fibrosis.. Matrix biology : journal of the International Society for Matrix Biology(IF=4.8). 2018. PMID:29221811. DOI: 10.1016/j.matbio.2017.11.011.
  • [56] Bizhen Wei;Jing Huang;Yu Zhang;Xiuxiu Hu;Cao Ma;Yiping Li;Pingsheng Chen. Restoration of RECK expression attenuates liver fibrosis induced by carbon tetrachloride through the Nrf2-MMP9 axis.. International immunopharmacology(IF=4.7). 2024. PMID:39476567. DOI: 10.1016/j.intimp.2024.113475.

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