Kai-Xin-San alleviates Alzheimer's disease by targeting the DHFR-mediated folate-mitochondrial axis
- J Ethnopharmacol. 2026 Apr 24:361:121230. doi: 10.1016/j.jep.2026.121230.
- 1. Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan province, China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, China.
- 2. School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, China.
- 3. Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan province, China.
- 4. Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan province, China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, China. Electronic address: [email protected].
- 5. Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan province, China; Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, China. Electronic address: [email protected].
- 6. School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, China. Electronic address: [email protected].
Ethnopharmacological relevance: Kai-Xin-San (KXS) is a classical herbal formula first recorded in the Tang Dynasty and has been used for more than 1000 years for cognitive impairment and dementia.
Aim of the study: To investigate whether KXS granules (KXSG) alleviate mitochondrial dysfunction in AD by engaging dihydrofolate reductase (DHFR) -linked folate metabolism.
Materials and methods: The pharmacodynamic effects of KXSG were evaluated in APP/PS1 transgenic mice using behavioral testing, neuropathological assessment, and ultrastructural examination of mitochondria. Pathways and candidate targets were first prioritized by brain-tissue DIA proteomics, and were further supported by a network pharmacology analysis based on putative brain-penetrant constituents. Mechanistic validation was performed both in vivo using APP/PS1 transgenic mice and in vitro using an APP-overexpressing HT22 cell model. Mitochondrial function, folate-cycle-related indices, and target protein expression were assessed in both systems, and pharmacological inhibition of DHFR with methotrexate was employed to probe causality.
Results: KXSG treatment improved learning and memory performance, preserved hippocampal neuronal integrity, and reduced Aβ burden in APP/PS1 mice. Proteomic profiling showed that proteins reversed by KXSG were enriched for mitochondrial localization and were closely linked to folate metabolism. DHFR emerged as a key candidate within this network. In cellular assays, KXSG mitigated AD-related mitochondrial impairment while partially normalizing folate-cycle-associated markers and DHFR expression. Notably, methotrexate, a DHFR inhibitor, attenuated the mitochondrial benefits conferred by KXSG.
Conclusion: These data support DHFR-associated folate metabolism as an important mechanistic axis through which KXSG promotes mitochondrial function in AD, providing experimental evidence for a folate-mitochondria link underlying its neuroprotective effects.
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Research Areas: Cancer
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