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

@article{li2026madecassic,
  title = {{Madecassic acid orchestrates DDX17-dependent pathway suppression of ferroptosis to mitigate myocardial ischemic/reperfusion injury}},
  author = {Wenlin Li and Sainan Li and Lin Dou and Xiuqing Huang and Kun Xu and Que Wang and Dachuan Guo and Xingyun Jiao and Liwei Zhang and Yang Wang and Ju Cui and Yong Man and Deping Liu and Tong Zou and Xue Yu and Liang Sun and Qiang Wang and Jian Li and Junpeng Gao and Tao Shen},
  journal = {Cellular \& Molecular Biology Letters},
  year = {2026},
  month = jul,
  doi = {10.1186/s11658-026-00950-8},
  url = {https://doi.org/10.1186/s11658-026-00950-8},
  note = {CC BY},
}

TY  - JOUR
TI  - Madecassic acid orchestrates DDX17-dependent pathway suppression of ferroptosis to mitigate myocardial ischemic/reperfusion injury
AU  - Wenlin Li
AU  - Sainan Li
AU  - Lin Dou
AU  - Xiuqing Huang
AU  - Kun Xu
AU  - Que Wang
AU  - Dachuan Guo
AU  - Xingyun Jiao
AU  - Liwei Zhang
AU  - Yang Wang
AU  - Ju Cui
AU  - Yong Man
AU  - Deping Liu
AU  - Tong Zou
AU  - Xue Yu
AU  - Liang Sun
AU  - Qiang Wang
AU  - Jian Li
AU  - Junpeng Gao
AU  - Tao Shen
PY  - 2026
DA  - 2026/07/01
JO  - Cellular & Molecular Biology Letters
DO  - 10.1186/s11658-026-00950-8
UR  - https://doi.org/10.1186/s11658-026-00950-8
AB  - 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
SN  - 1689-1392
SN  - 1425-8153
ER  -