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Background <p>Coronary heart disease (CHD) is the most prevalent and fatal cardiovascular disorder, with myocardial ischemia/reperfusion injury (MIRI) as its core pathogenic mechanism. Madecassic acid (MA), a pentacyclic triterpenoid isolated from <i>Centella asiatica</i>, has shown prominent cardioprotective activity. Nevertheless, the precise regulatory mechanisms underlying the protective effects of MA against MIRI remain to be elucidated.</p> Methods <p>A natural compound library was employed to screen natural drugs with anti-MIRI activity. The therapeutic efficacy of MA was evaluated in a primary cardiomyocyte hypoxia/reoxygenation model and a murine myocardial ischemia/reperfusion model. A series of experimental assays were applied to systematically assess the inflammatory response, mitochondrial function, and modes of cell death. RNA-seq, co-immunoprecipitation assays, and siRNA-mediated interference were utilized to explore downstream target molecules. Target gene knockout experiments were performed to validate the pharmacological effects and potential molecular mechanisms of MA.</p> Results <p>Through a well-established drug screening system, MA was identified as a promising compound that exerts a significant protective effect against MIRI. In vitro and in vivo experiments demonstrated that MA exerts potent cardioprotection through a hierarchical signaling network governed by DDX17. Mechanistically, MA modulates mitochondrial homeostasis and energy metabolism via a multi-pathway mechanism, and significantly suppresses&#xa0;reactive oxygen species (ROS) accumulation, thereby ultimately alleviating autophagic flux blockade and cardiomyocyte apoptosis. Furthermore, MA promotes the interaction between DDX17 and heat shock protein 90 (HSP90), which in turn enhances the phosphorylation of dynamin-related protein 1 (DRP1) at Ser637 and suppresses the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), thus preventing cardiomyocyte ferroptosis.</p> Conclusions <p>Collectively, this study identifies MA as a novel natural compound that activates DDX17 through multi-pathway regulation to attenuate oxidative stress, stabilize energy metabolism, and ultimately mitigate MIRI-induced cardiomyocyte death. These findings provide novel insights into the regulatory roles of DDX17 in cardiac injury and establish the translational medical potential of MA as a DDX17-targeting agent for the intervention of cardiovascular diseases.</p> Graphical abstract <p></p>

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Madecassic acid orchestrates DDX17-dependent pathway suppression of ferroptosis to mitigate myocardial ischemic/reperfusion injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Wenlin Li,
  • Sainan Li,
  • Lin Dou,
  • Xiuqing Huang,
  • Kun Xu,
  • Que Wang,
  • Dachuan Guo,
  • Xingyun Jiao,
  • Liwei Zhang,
  • Yang Wang,
  • Ju Cui,
  • Yong Man,
  • Deping Liu,
  • Tong Zou,
  • Xue Yu,
  • Liang Sun,
  • Qiang Wang,
  • Jian Li,
  • Junpeng Gao,
  • Tao Shen

摘要

Background

Coronary heart disease (CHD) is the most prevalent and fatal cardiovascular disorder, with myocardial ischemia/reperfusion injury (MIRI) as its core pathogenic mechanism. Madecassic acid (MA), a pentacyclic triterpenoid isolated from Centella asiatica, has shown prominent cardioprotective activity. Nevertheless, the precise regulatory mechanisms underlying the protective effects of MA against MIRI remain to be elucidated.

Methods

A natural compound library was employed to screen natural drugs with anti-MIRI activity. The therapeutic efficacy of MA was evaluated in a primary cardiomyocyte hypoxia/reoxygenation model and a murine myocardial ischemia/reperfusion model. A series of experimental assays were applied to systematically assess the inflammatory response, mitochondrial function, and modes of cell death. RNA-seq, co-immunoprecipitation assays, and siRNA-mediated interference were utilized to explore downstream target molecules. Target gene knockout experiments were performed to validate the pharmacological effects and potential molecular mechanisms of MA.

Results

Through a well-established drug screening system, MA was identified as a promising compound that exerts a significant protective effect against MIRI. In vitro and in vivo experiments demonstrated that MA exerts potent cardioprotection through a hierarchical signaling network governed by DDX17. Mechanistically, MA modulates mitochondrial homeostasis and energy metabolism via a multi-pathway mechanism, and significantly suppresses reactive oxygen species (ROS) accumulation, thereby ultimately alleviating autophagic flux blockade and cardiomyocyte apoptosis. Furthermore, MA promotes the interaction between DDX17 and heat shock protein 90 (HSP90), which in turn enhances the phosphorylation of dynamin-related protein 1 (DRP1) at Ser637 and suppresses the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), thus preventing cardiomyocyte ferroptosis.

Conclusions

Collectively, this study identifies MA as a novel natural compound that activates DDX17 through multi-pathway regulation to attenuate oxidative stress, stabilize energy metabolism, and ultimately mitigate MIRI-induced cardiomyocyte death. These findings provide novel insights into the regulatory roles of DDX17 in cardiac injury and establish the translational medical potential of MA as a DDX17-targeting agent for the intervention of cardiovascular diseases.

Graphical abstract