Fibulin-1 deficiency alleviates liver fibrosis by inhibiting hepatic stellate cell activation via the p38 MAPK pathway

作者：Wenshan Zhao, Jingyu Zhang, Qingdong Guo, Qi Wang, Hong Zhao, Fan Xiao, Ming Han, Ying Cao, Rui Ding, Aiting Yang, Wen Xie · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05647-3 · 被引用次数：5 · 研究领域：Liver physiology and pathology、Wnt/β-catenin signaling in development and cancer、Connective tissue disorders research

Elastin stabilization has been correlated with the reversibility of fibrosis. Fibulin-1 can participate in elastin assembly, which promotes its stabilization. However, the role of Fibulin-1 in liver fibrosis remains unknown. Here, we performed a proteomics analysis to identify notable changes in Fibulin-1 expression during continuous fibrosis progression and regression. Fibulin-1 expression was dramatically increased in the plasma of patients with cirrhosis as well as in liver fibrosis models and hepatic stellate cells (HSCs) treated with TGF-β1, and significant accumulation of Fibulin-1 was observed in chronic hepatitis B (CHB)- and metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis. Functional studies demonstrated that Fibulin-1 silencing inhibited HSC activation, while the opposite effects were observed for Fibulin-1 overexpression in vitro. Furthermore, transcriptomic analysis revealed that Fibulin-1 mediated p38 MAPK pathway activation, which was confirmed by the addition of a p38 MAPK inhibitor. More importantly, Fibulin-1 depletion in a CCl 4 -induced liver fibrosis model substantially ameliorated fibrosis progression, which was accompanied by decreased profibrogenic gene expression and decreased levels of insoluble elastin. Moreover, activation of the p38 MAPK pathway was inhibited in vivo. The expression of Fibulin-1D, rather than Fibulin-1C, was elevated during liver fibrogenesis, which suggested a major role for Fibulin-1D in liver fibrosis. ...