Ginsenoside CK, a major active metabolite of ginsenosides, ameliorates calcium overload-induced arrhythmias and myocardial oxidative injury by targeting CaMKII
- 1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- 2Corresponding author.
Abstract
Background: Calcium overload is a central pathological factor in cardiovascular disorders, including arrhythmia and myocardial injury. Recent studies suggest that ginsenoside metabolites may alleviate calcium overload; however, the principal active metabolite and its direct molecular target remain unclear. Methods: This study systematically screened the active components of enzymatically hydrolyzed total ginsenosides by integrating UPLC-Q/TOF-MS, principal component analysis, and calcium antagonistic activity assays. An alkynylated probe of the key active component was then synthesized for target identification using chemical biology approaches. Molecular biology methods were used to investigate the binding mechanisms. Rat models of arrhythmia and myocardial oxidative injury were further used to evaluate its pharmacological effects in vivo and to examine the associated signaling pathway. Results: The study revealed that the calcium antagonistic activity of ginsenosides was closely associated with secondary saponins, particularly ginsenoside CK (G-CK). CaMKII was identified as a key target through which G-CK alleviates calcium overload. G-CK bound to CaMKII and suppressed its autophosphorylation. Molecular biology experiments collectively supported an ATP-competitive mode of CaMKII inhibition by G-CK. Functionally, G-CK reduced intracellular calcium overload, attenuated mitochondrial Ca 2+ accumulation and ROS generation, and ameliorated calcium overload-induced arrhythmia and myocardial oxidative injury in vivo . Conclusion: These findings identify G-CK as a major active metabolite of ginsenosides that alleviates calcium overload-associated cardiac injury by targeting CaMKII. This work provides mechanistic insight into the cardiovascular protective effects of ginseng metabolites and suggests that G-CK may serve as a potential lead compound for the development of novel calcium antagonists.
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BibTeX
@article{xu2026ginsenoside,
title = {{Ginsenoside CK, a major active metabolite of ginsenosides, ameliorates calcium overload-induced arrhythmias and myocardial oxidative injury by targeting CaMKII}},
author = {Sihan Xu and Yixu Wang and Ziyue Zhang and Jin Zhang and Wei Yang and Wenjuan Liu and Min Jiang and Gang Bai},
journal = {Journal of Ginseng Research},
year = {2026},
month = jul,
doi = {10.1016/j.jgr.2026.101111},
url = {https://doi.org/10.1016/j.jgr.2026.101111},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Ginsenoside CK, a major active metabolite of ginsenosides, ameliorates calcium overload-induced arrhythmias and myocardial oxidative injury by targeting CaMKII
AU - Sihan Xu
AU - Yixu Wang
AU - Ziyue Zhang
AU - Jin Zhang
AU - Wei Yang
AU - Wenjuan Liu
AU - Min Jiang
AU - Gang Bai
PY - 2026
DA - 2026/07/15
JO - Journal of Ginseng Research
DO - 10.1016/j.jgr.2026.101111
UR - https://doi.org/10.1016/j.jgr.2026.101111
AB - Background: Calcium overload is a central pathological factor in cardiovascular disorders, including arrhythmia and myocardial injury. Recent studies suggest that ginsenoside metabolites may alleviate calcium overload; however, the principal active metabolite and its direct molecular target remain unclear. Methods: This study systematically screened the active components of enzymatically hydrolyzed total ginsenosides by integrating UPLC-Q/TOF-MS, principal component analysis, and calcium antagonistic activity assays. An alkynylated probe of the key active component was then synthesized for target identification using chemical biology approaches. Molecular biology methods were used to investigate the binding mechanisms. Rat models of arrhythmia and myocardial oxidative injury were further used to evaluate its pharmacological effects in vivo and to examine the associated signaling pathway. Results: The study revealed that the calcium antagonistic activity of ginsenosides was closely associated with secondary saponins, particularly ginsenoside CK (G-CK). CaMKII was identified as a key target through which G-CK alleviates calcium overload. G-CK bound to CaMKII and suppressed its autophosphorylation. Molecular biology experiments collectively supported an ATP-competitive mode of CaMKII inhibition by G-CK. Functionally, G-CK reduced intracellular calcium overload, attenuated mitochondrial Ca 2+ accumulation and ROS generation, and ameliorated calcium overload-induced arrhythmia and myocardial oxidative injury in vivo . Conclusion: These findings identify G-CK as a major active metabolite of ginsenosides that alleviates calcium overload-associated cardiac injury by targeting CaMKII. This work provides mechanistic insight into the cardiovascular protective effects of ginseng metabolites and suggests that G-CK may serve as a potential lead compound for the development of novel calcium antagonists.
SN - 1226-8453
SN - 2093-4947
ER -