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<p>Based on bioinformatics insights, this study investigates the functions of lysophosphatidic acid receptor 3 (LPAR3) and TEA domain transcription factor 4 (TEAD4) in hepatic stellate cell (HSC) activation and portal hypertension (PHT) progression. LPAR3 exhibited heightened expression in transforming growth factor beta 1-activated human HSCs (LX-2) and in the liver of carbon tetrachloride-challenged mice. Knockdown of LPAR3 alleviated activation and contractile activity of LX-2 cells, as well as ameliorated liver injury and fibrosis in PHT mice, achieved through deactivation of the p38 MAPK and PI3K/AKT signaling. TEAD4, which was enhanced in the activated LX-2 cells and the liver of PHT mice, was identified to bind to the promoter of LPAR3 to promote its transcription. Silencing of TEAD4 similarly inactivated the p38 MAPK and PI3K/AKT pathways by repressing LPAR3, thus alleviating LX-2 cell activation and liver fibrosis in PHT mice. However, these effects were negated by LPAR3 overexpression. In summary, this investigation suggests that TEAD4-mediated upregulation of LPAR3 augments HSC activation and liver fibrosis in PHT by inducing the p38 MAPK and PI3K/AKT axis.</p>

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TEAD4-mediated upregulation of LPAR3 augments hepatic stellate cell activation in portal hypertension

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Ruizhao Qi,
  • Zhengyao Chang,
  • Wenlei Zhao,
  • Yuxuan Qiu,
  • Weihua Chang,
  • Ying Zhang,
  • Xinglong Hu,
  • Zhiwei Li

摘要

Based on bioinformatics insights, this study investigates the functions of lysophosphatidic acid receptor 3 (LPAR3) and TEA domain transcription factor 4 (TEAD4) in hepatic stellate cell (HSC) activation and portal hypertension (PHT) progression. LPAR3 exhibited heightened expression in transforming growth factor beta 1-activated human HSCs (LX-2) and in the liver of carbon tetrachloride-challenged mice. Knockdown of LPAR3 alleviated activation and contractile activity of LX-2 cells, as well as ameliorated liver injury and fibrosis in PHT mice, achieved through deactivation of the p38 MAPK and PI3K/AKT signaling. TEAD4, which was enhanced in the activated LX-2 cells and the liver of PHT mice, was identified to bind to the promoter of LPAR3 to promote its transcription. Silencing of TEAD4 similarly inactivated the p38 MAPK and PI3K/AKT pathways by repressing LPAR3, thus alleviating LX-2 cell activation and liver fibrosis in PHT mice. However, these effects were negated by LPAR3 overexpression. In summary, this investigation suggests that TEAD4-mediated upregulation of LPAR3 augments HSC activation and liver fibrosis in PHT by inducing the p38 MAPK and PI3K/AKT axis.