
-   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

The TIMP1 gene encodes for tissue inhibitor of metalloproteinases-1, a protein that inhibits the activity of matrix metalloproteinases (MMPs) [CS: 10]. This inhibition is critical for balancing extracellular matrix (ECM) turnover, as MMPs are involved in ECM degradation [CS: 10]. TIMP1 by binding to MMPs' catalytic zinc cofactor, prevents the breakdown of ECM components, thus controlling tissue remodeling and maintaining tissue structure [CS: 9]. Additionally, TIMP1 has growth factor-like properties, promoting cell proliferation and affecting cell migration and apoptosis, potentially through cellular signaling involving CD63 and ITGB1 [CS: 8].

In the context of kidney diseases and toxic events, TIMP1 expression is frequently upregulated [CS: 9]. This upregulation serves as a countermeasure against ECM degradation and structural damage associated with pathological conditions [CS: 8]. For example, in renal ischemia-reperfusion injury and other nephropathies, increased TIMP1 levels may act to limit the extent of ECM breakdown mediated by MMPs, attempting to preserve kidney architecture and function [CS: 8]. However, in conditions such as renal interstitial fibrosis, persistent upregulation of TIMP1 contributes to ECM accumulation by inhibiting MMP activity, which paradoxically exacerbates tissue scarring [CS: 9]. Following injury and under the influence of inflammatory cytokines such as TGF-beta and TNF-alpha, upregulated TIMP1 expression also modulates cell survival and potentially affects angiogenesis, as these cytokines are known to activate cellular signaling cascades that include TIMP1 receptor interactions with CD63 and integrin beta 1 (ITGB1) [CS: 7]. Additionally, in the context of lupus nephritis, TIMP1-positive monocytes were identified through single-cell sequencing in the kidneys, suggesting that TIMP1 may be part of a localized immune response to limit the inflammation-driven damage characteristic of this autoimmune condition [CS: 8].
