
-   TIMP-1 is one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-beta-mediated crosstalk between HSCs and hepatocellular carcinoma (HCC) cells. TGF-beta signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Thus, TIMP-1 mediates TGF-beta-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling [PMID: 26549110].
-   TIMP1 mRNA expression in colon patients was augmented in stages I, II, III, and IV compared with that in adjacent normal mucosa. Expression levels of TIMP1 was also significantly correlated multiple metastasis and invasion related clinical parameters [PMID: 27644693].
-   Knockdown of TIMP1 inhibited the proliferation of colon cancer cells and significantly decreased SLUG, one important EMT transfactor, which lead to ascending of E-cadherin, and decline of Fibronectin, the mesenchymal marker, suggesting that TIMP1 may mediate epithelial-mesenchymal transition (EMT) initiation and colon progression. Meanwhile, TIMP1 could increase anti-apoptosis of colon cancer in BAD mediated phosphorylation pathway. The FAK-PI3K/AKT and MAPK pathway might participate in TIMP1-induced cell proliferation, metastasis and anti-apoptosis in colon cells [PMID: 27644693].
-   After liver injury, hepatic stellate cells (HSCs) express matrix-degrading enzymes in the early stages, transitioning to a pattern that preserves fibrillar collagens during later stages. The expression shift involves pro-MMP-2, MT1-MMP, and increased TIMP-1, contributing significantly to liver fibrosis progression. Upon cessation of liver injury, there is a reversal, marked by rapid TIMP-1 downregulation, heightened collagenase activity, and regression of liver fibrosis. In essence, TIMP-1 expression dynamics play a crucial role in balancing matrix degradation and fibrosis progression during different phases of liver injury and recovery [PMID: 11586466].

## Summary

TIMP1 encodes for tissue inhibitor of metalloproteinases-1, a protein that inhibits matrix metalloproteinases (MMPs) by binding to their catalytic zinc cofactor, leading to their irreversible inactivation. This action prevents the degradation of the extracellular matrix, which is crucial for maintaining tissue architecture and preventing excessive tissue remodeling.

In response to liver toxicity, such as hepatic injury or chronic hepatitis, hepatic stellate cells express TIMP-1. The upregulation of TIMP-1 mRNA is also observed upon lipocyte activation and is further increased in response to cytokines like tumor necrosis factor alpha. The elevated TIMP-1 levels contribute to the preservation of the extracellular matrix by inhibiting MMP activity and thus may prevent the excessive breakdown of matrix components during liver damage. However, this protective mechanism can become maladaptive, as persistent TIMP-1 expression can lead to the accumulation of extracellular matrix and progression of liver fibrosis, a pathological hallmark of chronic liver diseases. Additionally, TIMP-1 interacts with TGF-beta signaling pathways, promoting crosstalk between hepatic stellate and cancer cells, which enhances cellular adhesion and proliferation signaling, contributing to the development and progression of liver pathology.
