Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1<sup>N532/M550</sup> and promoting its degradation

Ying Zhang; Huan Lan; Wenjuan Zhai; Lin Jiang; Xiaotong Xia; Fang Liu; Lin Zhang; Jinjun Wu; Zhongqiu Liu; Caiyan Wang

doi:10.1016/j.jpha.2025.101219

Volume 15 Issue 11

Nov. 2025

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Ying Zhang, Huan Lan, Wenjuan Zhai, Lin Jiang, Xiaotong Xia, Fang Liu, Lin Zhang, Jinjun Wu, Zhongqiu Liu, Caiyan Wang. Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1N532/M550 and promoting its degradation[J]. Journal of Pharmaceutical Analysis, 2025, 15(11): 101219. doi: 10.1016/j.jpha.2025.101219

Citation:

Ying Zhang, Huan Lan, Wenjuan Zhai, Lin Jiang, Xiaotong Xia, Fang Liu, Lin Zhang, Jinjun Wu, Zhongqiu Liu, Caiyan Wang. Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1^N532/M550 and promoting its degradation[J]. Journal of Pharmaceutical Analysis, 2025, 15(11): 101219. doi: 10.1016/j.jpha.2025.101219

Citation:

Ying Zhang, Huan Lan, Wenjuan Zhai, Lin Jiang, Xiaotong Xia, Fang Liu, Lin Zhang, Jinjun Wu, Zhongqiu Liu, Caiyan Wang. Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1^N532/M550 and promoting its degradation[J]. Journal of Pharmaceutical Analysis, 2025, 15(11): 101219. doi: 10.1016/j.jpha.2025.101219

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Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1^N532/M550 and promoting its degradation

doi: 10.1016/j.jpha.2025.101219

State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 81930114 and U22A20368), the National Key Research and Development Program of China (Grant No.: 2017YFE0119900), and Guangzhou Basic and Applied Basic Research Project (Project No.: 202201011393).

Received Date: Sep. 17, 2024
Accepted Date: Jan. 24, 2025
Rev Recd Date: Jan. 19, 2025
Publish Date: Jan. 28, 2025

Abstract

Abstract

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.
- Oxidative stress,
- Caffeic acid,
- Acute myocardial ischemia-reperfusion,
- Keap1/Nrf2,
- Crystal structure

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References(49)

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