Restoration of RECK expression attenuates liver fibrosis induced by carbon tetrachloride through the Nrf2-MMP9 axis.

Liver fibrosis is a reversible process that can be delayed or even reversed through appropriate intervention during its development. The protein RECK, encoded by the Reck gene, regulates matrix metalloproteinase (MMP) activity and plays a crucial role in extracellular matrix (ECM) degradation and remodeling. Reduced RECK expression is found in various fibrotic tissues. However, the impact of restoring RECK expression on the development and progression of liver fibrosis has not yet been determined. This study found that the restoration of RECK expression attenuated TGF-β1-induced hepatic stellate cell (HSC) activation and mitigated carbon tetrachloride (CCl)-induced acute liver injury. In a mouse model of liver fibrosis induced by CCl, restoration of RECK expression reduced the degree of fibrosis, collagen deposition, and level of oxidative stress. RECK competes with Nrf2 for binding to Keap1, resulting in a decrease in the degradation of Nrf2 by Keap1 and an increase in the accumulation of Nrf2 in the cytoplasm. Under oxidative stress conditions, Nrf2 can be translocated to the nucleus for expression, initiating an antioxidant stress response, furthermore, Nrf2 can also activate MMP-9 and degrade the over-deposited collagen, thereby achieving the effect of alleviating liver fibrosis. Our study reveals a novel mechanism by which restoration of RECK expression ameliorates liver fibrosis, providing a promising target for combating liver fibrosis.