The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets.

The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.

Nerve growth factor orchestrates NGAL and matrix metalloproteinases activity to promote colorectal cancer metastasis.

PURPOSE: Colorectal cancer (CRC) is one most cancer type of high incidence and high mortality rate. Metastasis play an important role in survival rate and life quality of colorectal cancer patients. Nerve growth factor (NGF) has been shown to be involved in the metastasis and deterioration in many cancers, but the detail mechanisms in promoting the metastasis of colorectal cancer remain unknown. In this study, we aimed to explore the mechanism of NGF promoting colorectal cancer metastasis to provide new insights for developing NGF anti-colorectal cancer drugs. METHODS: We examined the expression of NGF in human colorectal cancer by immunohistochemical staining, and Western blot to evaluate the relationship between NGF and colorectal cancer metastasis. Using biochemical experiments including wound healing assay, transwell migration and invasion assay, RT-PCR, Western blot and ELISA to explore the relative mechanism of NGF promoting colorectal cancer cells metastasis in vivo. RESULTS: Our results found that the high expression of NGF was related with high incidence of metastasis. The binding of NGF to TrkA phosphorylated TrkA, which activated MAPK/Erk signaling pathway increasing the expression NGAL to enhance the activity of MMP2 and MMP9, promoted colorectal cancer metastasis. CONCLUSION: Our finding demonstrated that NGF increased NGAL expression to enhance MMPs activity to promoted colorectal cancer cell metastasis by TrkA-MAPK/Erk axis.

The dual roles of three MMPs and TIMP in innate immunity and metamorphosis in the silkworm, Bombyx mori.

The matrix metalloproteinases (MMPs) and their endogenous inhibitory factors, tissue inhibitors of metalloproteinases (TIMPs), are implicated in many diseases. However, the mammalian MMPs (> 20) and TIMPs (> 3) are larger in number, and so little is known about their individual roles in organisms. Hence, we have systematically studied the roles of all three MMPs and one TIMP in silkworm innate immunity and metamorphosis. We observed that MMPs and TIMP are highly expressed during the pupation stage of the silkworms, and TIMP could interact with each MMPs. High-activity MMPs and low-activity TIMP may enhance the infection of B. mori nucleopolyhedrovirus in both in vitro and in vivo. MMPs' knockout and TIMP overexpression delayed silkworm development and even caused death. Interestingly, different MMPs' knockout led to different tubular tissue dysplasia. These findings provide insights into the conserved functions of MMPs and TIMP in human organogenesis and immunoregulation.

Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis.

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.

Matrix metalloproteinases are involved in the development of neurological complications in patients with Coronavirus disease 2019.

BACKGROUND: Evidence show that Matrix metalloproteinases (MMPs) have been associated with neurological complications in the viral infections. Here in the current investigation, we intended to reveal if MMPs are potentially involved in the development of neurological symptoms in the patients with Coronavirus disease 2019 (COVID-19). METHODS: The levels of MMPs, inflammatory cytokines, chemokines, and adhesion molecules were evaluated in the serum and cerebrospinal fluid (CSF) samples from 10 COVID-19 patients with neurological syndrome (NS) and 10 COVID-19 patients lacking NS. Monocytes from the CSF samples were treated with TNF-α and the secreted levels of MMPs were determined. RESULTS: The frequency of monocytes were increased in the CSF samples of COVID-19 patients with NS compared to patients without NS. Levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α, chemokines CCL2, CCL3, CCL4, CCL7, CCL12, CXCL8, and CX3CL1, MMPs MMP-2, MMP-3, MMP-9, and MMP-12, and adhesion molecules ICAM-1, VCAM-1, and E-selectin were significantly increased in the CSF samples of COVID-19 patients with NS compared with patients without NS. Treatment of CSF-derived monocytes obtained from COVID-19 patients with NS caused increased production of MMP-2, MMP-3, MMP-9, and MMP-12. CONCLUSIONS: Higher levels of inflammatory cytokines might promote the expression of adhesion molecules on blood-CSF barrier (BCSFB), resulting in facilitation of monocyte recruitment. Increased levels of CSF chemokines might also help to the trafficking of monocytes to CSF. Inflammatory cytokines might enhance production of MMPs from monocytes, leading to disruption of BCSFB (and therefore further infiltration of inflammatory cells to CSF) in COVID-19 patients with NS.

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria.

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

Adalimumab Induces a Wound Healing Profile in Patients with Hidradenitis Suppurativa by Regulating Macrophage Differentiation and Matrix Metalloproteinase Expression.

Adalimumab (ADA) is the only Food and Drug Administration‒approved treatment for moderate-to-severe hidradenitis suppurativa, whereas etanercept and certolizumab-pegol have been shown to be ineffective, suggesting that the mechanism of action of ADA is distinct in hidradenitis suppurativa and may contribute to improved wound healing. Given that macrophages (Mϕs) play pivotal roles throughout the wound healing process, an in vitro Mϕ differentiation assay was carried out to assess the impact of TNF‒anti-TNF complexes on these cells. TNF‒ADA complexes exhibited stronger inhibitory effects on inflammatory Mϕ differentiation. Moreover, RNA sequencing revealed several unique wound healing profiles for TNF‒ADA‒treated inflammatory Mϕs, which were not observed for those treated with either TNF‒etanercept or TNF‒certolizumab-pegol complexes, including the inhibition of the matrix metalloproteinase (MMP) pathway. In addition, ADA administration was found to significantly reduce the levels of inflammatory MMP-1 and MMP-9 while promoting wound-healing MMP-13 and tissue inhibitor of metalloproteinases 2 levels in the circulation of the patients with hidradenitis suppurativa who responded to treatment. Our in vitro findings show that TNF‒ADA‒treated inflammatory Mϕs exhibit a distinct profile resembling wound healing. Moreover, ADA not only differentially regulates MMP expression in patients with hidradenitis suppurativa responding to the therapy but also potentially induces a transition to a profile suggestive of wound healing.

Platelets and Matrix Metalloproteinases: A Bidirectional Interaction with Multiple Pathophysiologic Implications.

Platelets contain and release several matrix metalloproteinases (MMPs), a highly conserved protein family with multiple functions in organism defense and repair. Platelet-released MMPs as well as MMPs generated by other cells within the cardiovascular system modulate platelet function in health and disease. In particular, a normal hemostatic platelet response to vessel wall injury may be transformed into pathological thrombus formation by platelet-released and/or by locally generated MMPs. However, it is becoming increasingly clear that platelets play a role not only in hemostasis but also in immune response, inflammation and allergy, atherosclerosis, and cancer development, and MMPs seem to contribute importantly to this role. A deeper understanding of these mechanisms may open the way to novel therapeutic approaches to the inhibition of their pathogenic effects and lead to significant advances in the treatment of cardiovascular, inflammatory, and neoplastic disorders.

A new MMP-mediated prodomain cleavage mechanism to activate bone morphogenetic proteins from the extracellular matrix.

Since their discovery as pluripotent cytokines extractable from bone matrix, it has been speculated how bone morphogenetic proteins (BMPs) become released and activated from the extracellular matrix (ECM). In contrast to TGF-ßs, most investigated BMPs are secreted as bioactive prodomain (PD)-growth factor (GF) complexes (CPLXs). Recently, we demonstrated that PD-dependent targeting of BMP-7 CPLXs to the extracellular fibrillin microfibril (FMF) components fibrillin-1 and -2 represents a BMP sequestration mechanism by rendering the GF latent. Understanding how BMPs become activated from ECM scaffolds such as FMF is crucial to elucidate pathomechanisms characterized by aberrant BMP activation and ECM destruction. Here, we describe a new MMP-dependent BMP-7 activation mechanism from ECM-targeted pools via specific PD degradation. Using Edman sequencing and mutagenesis, we identified a new and conserved MMP-13 cleavage site within the BMP-7 PD. A degradation screen with different BMP family PDs and representative MMP family members suggested utilization of the identified site in a general MMP-driven BMP activation mechanism. Furthermore, sandwich ELISA and solid phase cleavage studies in combination with bioactivity assays, single particle TEM, and in silico molecular docking experiments provided evidence that PD cleavage by MMP-13 leads to BMP-7 CPLX disintegration and bioactive GF release.

The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity.

The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase-a prostate-specific antigen-in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process.

In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient's health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.

Structure and Function of Human Matrix Metalloproteinases.

The extracellular matrix (ECM) is a macromolecules network, in which the most abundant molecule is collagen. This protein in triple helical conformation is highly resistant to proteinases degradation, the only enzymes capable of degrading the collagen are matrix metalloproteinases (MMPs). This resistance and maintenance of collagen, and consequently of ECM, is involved in several biological processes and it must be strictly regulated by endogenous inhibitors (TIMPs). The deregulation of MMPs activity leads to development of numerous diseases. This review shows MMPs complexity.

Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma.

Angiogenesis is the growth of new capillaries from the preexisting blood vessels. Glioblastoma (GBM) tumors are highly vascularized tumors, and glioma growth depends on the formation of new blood vessels. Angiogenesis is a complex process involving proliferation, migration, and differentiation of vascular endothelial cells (ECs) under the stimulation of specific signals. It is controlled by the balance between its promoting and inhibiting factors. Various angiogenic factors and genes have been identified that stimulate glioma angiogenesis. Therefore, attention has been directed to anti-angiogenesis therapy in which glioma proliferation is inhibited by inhibiting the formation of new tumor vessels using angiogenesis inhibitory factors and drugs. Here, in this review, we highlight and summarize the various molecular mediators that regulate GBM angiogenesis with focus on recent clinical research on the potential of exploiting angiogenic pathways as a strategy in the treatment of GBM patients.

A framework for understanding Kawasaki disease pathogenesis.

Kawasaki disease (KD) is a common vasculitis of childhood, typically affecting children under the age of five. Despite many aspects of its presentation that bear resemblence to acute infection, no causative infectious agent has been identified despite years of intense scrutiny. Unlike most infections, however, there are significant differences in racial predilection that suggest a strong genetic influence. The inflammatory response in KD specifically targets the coronary arteries, also unusual for an infectious condition. In this review, we discuss recent hypotheses on KD pathogenesis as well as new insights into the innate immune response and mechanisms behind vascular damage. The pathogenesis is complex, however, and remains inadequately understood.

Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-ß Signaling in Angiosarcoma.

Angiosarcoma is a rare malignant tumor derived from endothelial cells, and its prognosis is poor because advanced angiosarcoma is often resistant to taxane therapy. Endoglin (CD105) acts as a coreceptor for TGF-ß signaling and is overexpressed in tumor-associated endothelial cells and enhances tumor angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibodies in various types of malignancies. Here, we investigated the role of endoglin in the pathogenesis of angiosarcoma and whether endoglin inhibition results in antitumor activity. Endoglin was overexpressed in angiosarcoma, and its inhibition was effective in promoting apoptosis and the suppression of migration, invasion, tube formation, and Warburg effect in angiosarcoma cells. Knockdown of endoglin activated caspase 3/7 that is essential for apoptosis, reduced survivin levels, and decreased paxillin and vascular endothelial cadherin phosphorylation and matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-ß signaling, the antitumor effect of endoglin in angiosarcoma was not based on Smad signaling regulation but on non-Smad TGF-ß signaling. Taken together, these results indicated that endoglin could be a novel therapeutic target for angiosarcoma.

Transcriptomic analysis of the testicular fusion in Spodoptera litura.

BACKGROUND: Lepidoptera is one group of the largest plant-feeding insects and Spodoptera litura (Lepidoptera: Noctuidae) is one of the most serious agricultural pests in Asia countries. An interesting and unique phenomenon for gonad development of Lepidoptera is the testicular fusion. Two separated testes fused into a single one during the larva-to-pupa metamorphosis, which is believed to contribute to sperm production and the prevalence in field. To study the molecular mechanism of the testicular fusion, RNA sequencing (RNA-seq) experiments of the testes from 4-day-old sixth instar larvae (L6D4) (before fusion), 6-day-old sixth instar larvae (L6D6, prepupae) (on fusing) and 4-day-old pupae (P4D) (after fusion) of S. litura were performed. RESULTS: RNA-seq data of the testes showed that totally 12,339 transcripts were expressed at L6D4, L6D6 and P4D stages. A large number of differentially expressed genes (DEGs) were up-regulated from L6D4 to L6D6, and then more genes were down-regulated from L6D6 to P4D. The DEGs mainly belongs to the genes related to the 20E signal transduction pathway, transcription factors, chitin metabolism related enzymes, the families of cytoskeleton proteins, extracellular matrix (ECM) components, ECM-related protein, its receptor integrins and ECM-remodeling enzymes. The expression levels of these genes that were up-regulated significantly during the testicular fusion were verified by qRT-PCR. The matrix metalloproteinases (MMPs) were found to be the main enzymes related to the ECM degradation and contribute to the testicular fusion. The testis was not able to fuse if MMPs inhibitor GM6001 was injected into the 5th abdomen region at L6D6 early stage. CONCLUSIONS: The transcriptome and DEGs analysis of the testes at L6D4, L6D6 and P4D stages provided genes expression information related to the testicular fusion in S. litura. These results indicated that cytoskeleton proteins, ECM-integrin interaction genes and ECM-related proteins were involved in cell migration, adhesion and fusion during the testicular fusion. The ECM degradation enzymes MMPs probably play a critical role in the fusion of testis.

MMP-mediated modulation of ECM environment during axonal growth and NMJ development.

Motor neurons, skeletal muscles, and perisynaptic Schwann cells interact with extracellular matrix (ECM) to form the tetrapartite synapse in the peripheral nervous system. Dynamic remodeling of ECM composition is essential to diversify its functions for distinct cellular processes during neuromuscular junction (NMJ) development. In this review, we give an overview of the proteolytic regulation of ECM proteins, particularly by secreted and membrane-type matrix metalloproteinases (MMPs), in axonal growth and NMJ development. It is suggested that MMP-2, MMP-9, and membrane type 1-MMP (MT1-MMP) promote axonal outgrowth and regeneration upon injury by clearing the glial scars at the lesion site. In addition, these MMPs also play roles in neuromuscular synaptogenesis, ranging from spontaneous formation of synaptic specializations to activity-dependent synaptic elimination, via proteolytic cleavage or degradation of growth factors, neurotrophic factors, and ECM molecules. For instance, secreted MMP-3 has been known to cleave agrin, the main postsynaptic differentiation inducer, further highlighting the importance of MMPs in NMJ formation and maintenance. Furthermore, the increased level of several MMPs in myasthenia gravis (MG) patient suggest the pathophysiological mechanisms of MMP-mediated proteolytic degradation in MG pathogenesis. Finally, we speculate on potential major future directions for studying the regulatory functions of MMP-mediated ECM remodeling in axonal growth and NMJ development.

[Development of Novel Nuclear Medical Imaging Probes for Quantification of Matrix Metalloproteinases in Diseases].

Matrix metalloproteinases (MMPs) regulate various cellular functions, such as motility, invasion, differentiation, and apoptosis. Precise in vivo quantification of MMPs in disease can provide beneficial information for both basic and clinical research studies. To this end, various types of probes have been developed for imaging MMPs in vivo. In this review, representative MMP-targeted probes, such as binding probes and activatable probes, are outlined, including highlights of our own research. In addition, strategies for the development of probes that apply "theranostics," a concept that integrates therapy and diagnostics, are elucidated with reference to [18F]IPFP, a new probe developed in our laboratory. [18F]IPFP was prepared by iodination of a known MMP inhibitor to enhance its affinity and labeled with the compact prosthetic agent 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP) for MMP-targeted positron-emission tomography (PET) and other therapeutic properties. IPFP demonstrated high inhibitory activity toward MMP-12 (IC50 value=1.5 nM). Radioactivity accumulation in the lungs 90 min after administration of [18F]IPFP was 4-fold higher in chronic obstructive pulmonary disease (COPD) mice overexpressing MMPs compared with normal mice. Ex vivo PET confirmed the radioactivity distribution in tissues, and autoradiography analysis demonstrated accumulation differences between COPD and normal mice. Consequently, [18F]IPFP showed potent inhibitory activities against MMPs and suitable pharmacokinetics for imaging pulmonary disease. Thus, [18F]IPFP is a promising theranostic probe for pulmonary disease and is expected to be applied to various other MMP-related diseases. Strategies for MMP probe development introduced in this review are anticipated to lead to the development of superior imaging probes in the future.

Matrix Mechanics as Regulatory Factors and Therapeutic Targets in Hepatic Fibrosis.

The hallmark of liver fibrosis is excessive extracellular matrix (ECM) synthesis and deposition that improve liver matrix remodeling and stiffening. Increased matrix stiffness is not only a pathological consequence of liver fibrosis in traditional view, but also recognized as a key driver in pathological progression of hepatic fibrosis. Cells can perceive changes in the mechanical characteristics of hepatic matrix and respond by means of mechanical signal transduction pathways to regulate cell behavior. In this review, the authors first classify causes of liver matrix stiffening during fibrotic progression, such as higher degree of collagen cross-linking. The latest advances of the research on the matrix mechanics in regulating activation of HSCs or fibroblasts under two-dimensional (2D) and three-dimensional (3D) microenvironment is also classified and summarized. The mechanical signaling pathways involved in the process of hepatic matrix stiffening, such as YAP-TAZ signaling pathway, are further summarized. Finally, some potential therapeutic concepts and strategies based on matrix mechanics will be detailed. Collectively, these findings reinforce the importance of matrix mechanics in hepatic fibrosis, and underscore the value of clarifying its modulation in hopes of advancing the development of novel therapeutic targets and strategies for hepatic fibrosis.