Scholarlink

Background <p>Endothelial-to-mesenchymal transition (EndMT) has emerged as a pivotal pathological process during liver fibrosis. Angiotensin II receptor type 1 (AT1R) has been implicated in the regulation of EndMT and is considered a promising target for therapeutic intervention. Consequently, the identification of specific AT1R inhibitors may offer a novel approach to alleviate the liver fibrosis.</p> Purpose <p>This study aims to evaluate the potential of Betulinic Acid (BA) as a natural AT1R inhibitor and investigate its underlying mechanisms in the context of EndMT and liver fibrosis treatment.</p> Method <p>The binding interaction between BA and AT1R was evaluated using AlphaFold 3 (AF3) predictions, molecular dynamics (MD) simulations, and in vivo validation through <i>At1r</i> gene knockout in animals. A mouse model of liver fibrosis, induced by a Western diet combined with CCl<sub>4</sub>, along with human umbilical vein endothelial cells (HUVECs) treated with angiotensin II (Ang II), were utilized to assess the therapeutic efficacy of BA in the context of liver fibrosis and EndMT. To elucidate the pharmacological mechanisms underlying BA’s inhibition of EndMT, analyses including RNA sequencing (RNA-seq), hepatic endothelial cell magnetic bead sorting, Western blotting, and immunofluorescence staining were employed.</p> Result <p>AF3 and MD simulations revealed stable binding between BA and AT1R, which was further confirmed in the <i>At1r</i> knockout mouse model. Pharmacodynamic studies indicated that long-term oral administration of BA did not induce significant pathological alterations in liver and kidney functions, blood routine, or major organs in mice. However, notable improvements in liver fibrosis-related pathological indicators were observed. Further pharmacological analysis demonstrated that BA treatment substantially inhibited EndMT in the context of liver fibrosis, with the PI3K-AKT signaling pathway in endothelial cells identified as a potential mechanism.</p> Conclusion <p>This study presents the first evidence that BA alleviates liver fibrosis by acting as an AT1R antagonist to inhibit EndMT. These findings underscore the potential therapeutic application of BA as an AT1R inhibitor in the management of liver fibrosis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Betulinic acid as a novel AT1R inhibitor: attenuation of liver fibrosis via modulation of endothelial–mesenchymal transition in chronic hepatic injury

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月13日

查看全文
  • Bingwen Zhu,
  • Xiyu Dai,
  • Chunyan Liu,
  • Tao Bi,
  • Shenglu Liu,
  • Lei Chen,
  • Ting Wang,
  • Qixin Zhao,
  • Xinyue Liu,
  • Qin Sun,
  • Yingcheng Yang,
  • Zengjin Liu

摘要

Background

Endothelial-to-mesenchymal transition (EndMT) has emerged as a pivotal pathological process during liver fibrosis. Angiotensin II receptor type 1 (AT1R) has been implicated in the regulation of EndMT and is considered a promising target for therapeutic intervention. Consequently, the identification of specific AT1R inhibitors may offer a novel approach to alleviate the liver fibrosis.

Purpose

This study aims to evaluate the potential of Betulinic Acid (BA) as a natural AT1R inhibitor and investigate its underlying mechanisms in the context of EndMT and liver fibrosis treatment.

Method

The binding interaction between BA and AT1R was evaluated using AlphaFold 3 (AF3) predictions, molecular dynamics (MD) simulations, and in vivo validation through At1r gene knockout in animals. A mouse model of liver fibrosis, induced by a Western diet combined with CCl4, along with human umbilical vein endothelial cells (HUVECs) treated with angiotensin II (Ang II), were utilized to assess the therapeutic efficacy of BA in the context of liver fibrosis and EndMT. To elucidate the pharmacological mechanisms underlying BA’s inhibition of EndMT, analyses including RNA sequencing (RNA-seq), hepatic endothelial cell magnetic bead sorting, Western blotting, and immunofluorescence staining were employed.

Result

AF3 and MD simulations revealed stable binding between BA and AT1R, which was further confirmed in the At1r knockout mouse model. Pharmacodynamic studies indicated that long-term oral administration of BA did not induce significant pathological alterations in liver and kidney functions, blood routine, or major organs in mice. However, notable improvements in liver fibrosis-related pathological indicators were observed. Further pharmacological analysis demonstrated that BA treatment substantially inhibited EndMT in the context of liver fibrosis, with the PI3K-AKT signaling pathway in endothelial cells identified as a potential mechanism.

Conclusion

This study presents the first evidence that BA alleviates liver fibrosis by acting as an AT1R antagonist to inhibit EndMT. These findings underscore the potential therapeutic application of BA as an AT1R inhibitor in the management of liver fibrosis.