LXN-THBS2 Signaling Axis Regulates Hepatic Stellate Cell Activation and Promotes the Development of Liver Fibrosis.

Abstract

BACKGROUND: Liver fibrosis, the end-stage pathological state of many liver diseases, is primarily driven by the activation of hepatic stellate cells (HSCs) and collagen deposition resulting from various pathogenic causes. Thrombospondin-2 (THBS2), a secreted extracellular matrix glycoprotein encoded by the, has been found to activate the TLR4-transforming growth factor-β (TGF-β)/FAK signaling axis and HSCs through autocrine signalling, thereby contributing to the development of liver fibrosis. Latexin (LXN), the only known zinc-dependent metallocarboxypeptidase inhibitor in humans, has not yet been studied for its role in liver fibrosis is yet to be studied. METHODS: In this study, we used adeno-associated virus 9 (AAV9) to generate a mouse model of liver fibrosis with LXN knockdown and used siLXN to knock down the LXN gene in the human hepatic stellate cell line LX-2. The mechanisms underlying the association between LXN and hepatic fibrosis progression were investigated using quantitative polymerase chain reaction, western blot, immunohistochemistry, and immunofluorescence staining. RESULTS: LXN knockdown reduced carbon tetrachloride (CCl)-induced liver injury and suppressed activation of hepatic stellate cells, while also inhibiting the expression of α-SMA and collagen I. Furthermore, LXN demonstrates a substantial positive correlation with THBS2, and LXN knockdown was capable of downregulating THBS2. CONCLUSION: The LXN-THBS2 signaling axis may promote liver fibrosis progression by inducing the activation of HSCs.