Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, that is, tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Previous in vivo and in vitro studies of our laboratory found repressing extracellular matrix (ECM) accumulation by restoring the balance between MMPs and TIMPs can alleviate liver fibrosis. We conducted a review of articles published in PubMed and Science Direct in the last decade until February 1, 2023, which were searched for using these words "MMPs/TIMPs" and "Hepatic Fibrosis." Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs. We found the MMP-TIMP-ECM interaction can result in better understanding of the pathogenesis and progression of hepatic fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for hepatic fibrosis. Additionally, we summarized and analyzed the drugs that have been found to reduce liver fibrosis by changing the ratio of MMPs/TIMPs, including medicine natural products.

Keratoconus (KC) is a bilateral and noninflammatory disease, characterized by progressive thinning and anterior protrusion of the cornea and may result in severe visual impairment due to irregular astigmatism. Matrix metalloproteinases (MMP) are the main group of enzymes that degrade extracellular matrix proteins including collagens; Type IV collagen is found in the corneal stroma. MMP enzymatic activity is inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1). A decrease in TIMP-1 level is associated with the development of KC. In the present study, we investigated the impact of COL4A4 rs2228557 C/T and TIMP-1 rs4898 C/T (X-chromosome) variants on the odds of KC development in a sample of Iranian population.

This case-control study was conducted on 140 patients with KC and 150 healthy control subjects. We used modified methods of Nested-PCR and ARMS-PCR in combination (Nested-ARMS-PCR) and confirmed their validity with RFLP-PCR.

Significant differences were noticed between KC patients and healthy individuals regarding the genotype TY or T allele frequencies of rs4898 in the male subjects (OR = 0.43, 95%CI: 0.20-0.92, P = 0.03), whereas no significant differences were identified in the female subjects (OR = 1.07, 95%CI: 0.52-2.20, P = 0.85). The rs2228557, T allele was associated with KC (OR = 0.69, 95% CI: 0.50-0.97, P = 0.035).

In the rs2228557 variant, T allele acts as a protective factor from the disease and decreases the risk of KC compared with the C allele. Also, in our investigation about rs4898, we found that TY genotype or T allele decreased the risk of KC compared with the C allele in males and was a protective factor for KC in our population.

Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the hedgehog signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis.

The aim of this review is to describe the present knowledge about the hedgehog signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of hedgehog signaling pathway research. Moreover, we will discuss the different interactions with hedgehog signaling pathway-regulated liver fibrosis.

The hedgehog pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the hedgehog pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of hedgehog signaling pathway activation in liver fibrosis and HSC fate, including DNA methylation, methyl CpG binding protein 2, microRNA, irradiation and metabolism that influence hedgehog signaling pathway transduction. These findings identify the hedgehog pathway as a potentially important for biomarker development and therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective hedgehog-based drugs.

To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage.

Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OS-induced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography.

Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT.

Under conditions with an insufficient liver remnant, prevention of OS-induced damage via the Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery.

Fibrogenic cytokines, such as transforming growth factor-beta 1 play a central role in the progression of liver fibrosis. Recently, functional gene polymorphisms in these cytokines have been identified, and some reports have validated the presence of associations between these polymorphisms and disease progression. Connective tissue growth factor (CTGF) is a stimulating factor for fibroblast proliferation and matrix production. This study aimed to examine the relationship between CTGF gene polymorphisms and the progression of hepatitis C virus (HCV)-related chronic liver disease, as well as the incidence and prognosis of hepatocellular carcinoma (HCC).

A review was conducted among 235 HCV patients (117 patients with chronic hepatitis (CH) and 118 patients with liver cirrhosis (LC)). The CTGF gene polymorphism (rs6918698; -945 G/C) was identified according to the chimeric cycling probe method. The rate of liver fibrosis progression was measured using two liver fibrosis prediction formulas, the Forns index and the FibroIndex. All HCC patients were followed regularly every month.

The frequency of the -945 C allele was higher among the LC patients than the CH patients. Regarding the rate of liver fibrosis progression over five years, C homozygotes tended to exhibit a faster rate than G carriers, although the difference was not significant. Among the LC patients, the C homozygotes demonstrated lower prothrombin times, higher rates of indocyanine green retention and higher Child-Pugh scores than the G carriers. There were no significant tendencies in the genotype distribution, irrespective of the status of HCC. However, the prognosis of HCC was poorer for the C homozygotes than for the G carriers.

A CTGF -945 C homozygote status is a significant risk factor for the progression of HCV-related chronic liver disease, including HCC.