Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway
IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline; recent studies suggest that neuronal ferroptosis plays a key role in its pathogenesis. Danggui Shaoyao San (DSS), a traditional Chinese medicine formula, has shown demonstrated neuroprotective ef...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1588375/full |
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| author | Kai Gong Shuang Zhou Li Xiao Mengzhen Xu Yuhe Zhou Kaihui Lu Xin Yu Jiang Zhu Chuanguo Liu Qingjun Zhu Qingjun Zhu |
| author_facet | Kai Gong Shuang Zhou Li Xiao Mengzhen Xu Yuhe Zhou Kaihui Lu Xin Yu Jiang Zhu Chuanguo Liu Qingjun Zhu Qingjun Zhu |
| author_sort | Kai Gong |
| collection | DOAJ |
| description | IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline; recent studies suggest that neuronal ferroptosis plays a key role in its pathogenesis. Danggui Shaoyao San (DSS), a traditional Chinese medicine formula, has shown demonstrated neuroprotective effects, but its precise mechanisms in AD treatment remain unclear. This study aims to investigate the mechanism of DSS in treating AD by inhibiting neuronal ferroptosis, explore whether DSS alleviates AD by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 pathway.MethodsChemical composition of DSS was identified by LC-MS/MS, followed by network pharmacology to predict targets and pathways. Molecular docking assessed binding affinities between DSS compounds and key proteins (AMPK, Sp1, ACSL4). In vivo experiments on APP/PS1 mice evaluated DSS effects on cognitive function, oxidative stress markers, lipid peroxidation, and ferroptosis-related proteins.ResultsNetwork pharmacology analysis suggested that DSS regulates lipid metabolism and inhibits neuronal ferroptosis via the AMPK pathway. Molecular docking revealed strong binding affinities between DSS compounds and AMPK downstream proteins, Sp1 and ACSL4. In vivo experiments showed that DSS improved cognitive function, enhanced antioxidant capacity, reduced lipid peroxide accumulation, and decreased Fe2+ content in brain tissue. Furthermore, DSS increased the expression of FTH, p-AMPK, and GPX4 while decreasing Sp1 and ACSL4 levels, thereby inhibiting ferroptosis.ConclusionDSS alleviates AD symptoms by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 axis, representing a novel lipid metabolism-targeted therapeutic strategy. |
| format | Article |
| id | doaj-art-10eaae76ddf14ee39336c356cb47e015 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-10eaae76ddf14ee39336c356cb47e0152025-08-20T02:16:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15883751588375Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathwayKai Gong0Shuang Zhou1Li Xiao2Mengzhen Xu3Yuhe Zhou4Kaihui Lu5Xin Yu6Jiang Zhu7Chuanguo Liu8Qingjun Zhu9Qingjun Zhu10Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaCollege of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, ChinaAffiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaExperimental Center, Shandong University of Traditional Chinese Medicine, Jinan, ChinaInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaKey Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Jinan, ChinaIntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline; recent studies suggest that neuronal ferroptosis plays a key role in its pathogenesis. Danggui Shaoyao San (DSS), a traditional Chinese medicine formula, has shown demonstrated neuroprotective effects, but its precise mechanisms in AD treatment remain unclear. This study aims to investigate the mechanism of DSS in treating AD by inhibiting neuronal ferroptosis, explore whether DSS alleviates AD by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 pathway.MethodsChemical composition of DSS was identified by LC-MS/MS, followed by network pharmacology to predict targets and pathways. Molecular docking assessed binding affinities between DSS compounds and key proteins (AMPK, Sp1, ACSL4). In vivo experiments on APP/PS1 mice evaluated DSS effects on cognitive function, oxidative stress markers, lipid peroxidation, and ferroptosis-related proteins.ResultsNetwork pharmacology analysis suggested that DSS regulates lipid metabolism and inhibits neuronal ferroptosis via the AMPK pathway. Molecular docking revealed strong binding affinities between DSS compounds and AMPK downstream proteins, Sp1 and ACSL4. In vivo experiments showed that DSS improved cognitive function, enhanced antioxidant capacity, reduced lipid peroxide accumulation, and decreased Fe2+ content in brain tissue. Furthermore, DSS increased the expression of FTH, p-AMPK, and GPX4 while decreasing Sp1 and ACSL4 levels, thereby inhibiting ferroptosis.ConclusionDSS alleviates AD symptoms by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 axis, representing a novel lipid metabolism-targeted therapeutic strategy.https://www.frontiersin.org/articles/10.3389/fphar.2025.1588375/fullAlzheimer’s diseaseneuron ferroptosisAMPK/Sp1/ACSL4 pathwayDanggui Shaoyao Sanlipid metabolism |
| spellingShingle | Kai Gong Shuang Zhou Li Xiao Mengzhen Xu Yuhe Zhou Kaihui Lu Xin Yu Jiang Zhu Chuanguo Liu Qingjun Zhu Qingjun Zhu Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway Frontiers in Pharmacology Alzheimer’s disease neuron ferroptosis AMPK/Sp1/ACSL4 pathway Danggui Shaoyao San lipid metabolism |
| title | Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway |
| title_full | Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway |
| title_fullStr | Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway |
| title_full_unstemmed | Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway |
| title_short | Danggui Shaoyao San ameliorates Alzheimer’s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway |
| title_sort | danggui shaoyao san ameliorates alzheimer s disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the ampk sp1 acsl4 signaling pathway |
| topic | Alzheimer’s disease neuron ferroptosis AMPK/Sp1/ACSL4 pathway Danggui Shaoyao San lipid metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1588375/full |
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