MKL1 promotes endothelial-to-mesenchymal transition and liver fibrosis by activating TWIST1 transcription

Zilong Li, Baoyu Chen, Wenhui Dong, Ming Kong, Zhiwen Fan, Liming Yu, Dongmei Wu, Jun Lu, Yong Xu

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Sinusoidal endothelial cells contribute to myofibroblast activation and liver fibrosis by undergoing endothelial-mesenchymal transition (EndMT). The underlying mechanism remains poorly defined. Here we report that inhibition or endothelial-specific deletion of MKL1, a transcriptional modulator, attenuated liver fibrosis in mice. MKL1 inhibition or deletion suppressed EndMT induced by TGF-β. Mechanistically, MKL1 was recruited to the promoter region of TWIST1, a master regulator of EndMT, and activated TWIST1 transcription in a STAT3-dependent manner. A small-molecule STAT3 inhibitor (C188-9) alleviated EndMT in cultured cells and bile duct ligation (BDL) induced liver fibrosis in mice. Finally, direct inhibition of TWIST1 by a small-molecule compound harmine was paralleled by blockade of EndMT in cultured cells and liver fibrosis in mice. In conclusion, our data unveil a novel mechanism underlying EndMT and liver fibrosis and highlight the possibility of targeting the STAT3-MKL1-TWIST1 axis in the intervention of aberrant liver fibrogenesis.

Original languageEnglish (US)
Article number899
JournalCell Death and Disease
Issue number12
StatePublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cancer Research
  • Cell Biology
  • Immunology


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