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Ginsenoside compound K alleviates brain aging by inhibiting ferroptosis through modulation of the ASK1-MKK7-JNK
Xiaojun Yan1, Xue Bai2, Guanghui Sun1
1Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710127, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710127, China.
Background:
Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.
Purpose:
This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways.
Methods:
We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection.
Results:
Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging.
Conclusion:
In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.
Insights
Ginsenoside compound K (CK) delays brain aging by targeting the ASK1-MKK7-JNK pathway, boosting Nrf2, and reducing ferroptosis. This suggests CK is a promising therapeutic for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Gerontology
- Pharmacology
Background:
- Brain aging contributes to neurodegenerative diseases.
- Current treatments have limitations.
- Ginsenoside compound K (CK) shows antioxidant promise.
Purpose of the Study:
- Elucidate CK's impact on brain senescence.
- Investigate CK's role in oxidative stress pathways.
Main Methods:
- Used d-galactose-induced PC-12 senescent cells and mouse brain aging models.
- Assessed mitochondrial function via immunofluorescence and western blotting.
- Investigated molecular mechanisms using transcriptomics and western blotting; validated ASK1 targeting.
Main Results:
- CK alleviated cognitive decline and neuronal damage in aging models.
- CK enhanced antioxidant enzyme activity and restored mitochondrial function.
- CK inhibited ferroptosis by upregulating SLC7A11 and GPX4, targeting ASK1 to suppress MKK7/JNK, and promoting Nrf2 nuclear accumulation.
Conclusions:
- CK delays brain aging by inhibiting the ASK1-MKK7-JNK pathway.
- CK enhances nuclear Nrf2 expression and suppresses ferroptosis.
- CK is a potential therapeutic for brain aging and neurodegenerative diseases.
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