ZLY032 mediated activation of Notch1/Hes1 signaling inhibits cardiomyocyte ferroptosis to protect against myocardial Ischemia-Reperfusion injury in mice

  • Biochem Pharmacol. 2025 Sep:239:117039. doi: 10.1016/j.bcp.2025.117039.
Hao-Dong Li  1 ,  Dong-Ping Liu  1 ,  Man-Yu Gong  1 ,  Ying Zhang  1 ,  Jie Liu  1 ,  Jun-Ting Ren  1 ,  Meng-Xing Cheng  1 ,  Yan-Wei Zhang  1 ,  Hao Wang  1 ,  Si-Yu Wang  1 ,  Jian Huang  2 ,  Xue Feng  3 ,  Sen-Qing Jiang  3 ,  Xin Li  4 ,  Tong Liu  1 ,  Ming-Yu Yang  1 ,  Wei Liu  1 ,  Lei Jiao  5 ,  Meng-Meng Li  6 ,  Ying Zhang  7
Affiliations
  • 1. Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China.
  • 2. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 3. Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 4. Department of Cardiovascular Sciences, School of Engineering, University of Leicester, Leicester, UK.
  • 5. Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: [email protected].
  • 6. Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China. Electronic address: [email protected].
  • 7. Ultrasound Imaging Department of the Second Affiliated Hospital of Harbin Medical University, and State-Province Key Laboratories of Biomedicine-Pharmaceutics, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: [email protected].
PMID: 40499841 DOI: 10.1016/j.bcp.2025.117039
Abstract

Myocardial ischemia/reperfusion (I/R) injury seriously compromises patients' prognosis and survival rates. Accumulating evidence shows that Ferroptosis is intricately involved in myocardial I/R injury. The activation of Notch1 exerts a protective effect on the heart. However, whether it plays a cardioprotective role by inhibiting cardiomyocyte Ferroptosis and what the underlying mechanisms are remain unclear. Here, we found that activating the Notch1/Hes1 signaling pathway during the ischemia/reperfusion (I/R) can effectively inhibit the levels of lipid peroxidation and oxidative stress in cardiomyocytes, thereby suppressing myocardial Ferroptosis. In addition, we identified a small molecule compound, ZLY032, which is an agonist of PPARδ and possesses anti-inflammatory and antioxidant activities. Treatment with ZLY032 potently alleviated I/R-mediated cardiac contractile impairment, decreased the infarct area and mitigated cardiomyocyte Ferroptosis. Mechanistically, the Notch intracellular domain (NICD)interacts with GPX4 to inhibit its degradation. As a PPARδ Agonist, ZLY032 activates the Notch1/Hes1 signaling pathway in a PPARδ-dependent manner, thereby inhibiting myocardial Ferroptosis and exerting a cardioprotective effect. In conclusion, our study elucidates that Notch1 inhibits cardiomyocyte Ferroptosis by modulating the protein stability of GPX4. Moreover, ZLY032 serves as a novel protective agent against myocardial ischemia-reperfusion injury， exerts its effects by relying on PPARδ-mediated upregulation of the Notch1/Hes1 signaling pathway and the subsequent reinforcement of GPX4 protein stability, highlighting the potential of ZLY032 as a promising therapeutic agent for treating myocardial I/R injury.

Keywords
Ferroptosis; GPX4; Myocardial ischemia/reperfusion injury; Notch1; PPARδ; ZLY032.
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