Department of Pathology, School of Medicine, Southeast University, Nanjing, China.
Department of Pathology, School of Medicine, Southeast University, Nanjing, China; Department of Respiratory and Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113475. doi: 10.1016/j.intimp.2024.113475. Epub 2024 Oct 29.
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.
肝纤维化是一个可逆转的过程，可以通过在其发展过程中进行适当的干预来延迟甚至逆转。蛋白 RECK 由 Reck 基因编码，调节基质金属蛋白酶（MMP）的活性，在细胞外基质（ECM）降解和重塑中发挥关键作用。在各种纤维化组织中发现 RECK 的表达减少。然而，恢复 RECK 表达对肝纤维化的发展和进展的影响尚未确定。本研究发现，恢复 RECK 表达可减弱 TGF-β1 诱导的肝星状细胞（HSC）激活，并减轻四氯化碳（CCl）诱导的急性肝损伤。在 CCl 诱导的肝纤维化小鼠模型中，恢复 RECK 表达可降低纤维化程度、胶原沉积和氧化应激水平。RECK 与 Nrf2 竞争与 Keap1 的结合，导致 Keap1 对 Nrf2 的降解减少和细胞质中 Nrf2 的积累增加。在氧化应激条件下，Nrf2 可以转移到细胞核中进行表达，启动抗氧化应激反应，此外，Nrf2 还可以激活 MMP-9 并降解过度沉积的胶原，从而达到缓解肝纤维化的效果。我们的研究揭示了恢复 RECK 表达改善肝纤维化的一种新机制，为对抗肝纤维化提供了一个有前途的靶点。
