{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:07Z","timestamp":1790661907943,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019446","name":"Medical and Health Science and Technology Development Project of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019446","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020196","name":"Shandong Provincial Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alzheimer\u2019s disease (AD) and its prodromal mild cognitive impairment (MCI) lack effective disease-modifying therapeutic strategies. Gastrodin (GAS), the major bioactive compound of\n                      <jats:italic>Gastrodia elata<\/jats:italic>\n                      , exhibits pronounced neuroprotective effects. However, the precise candidate molecular targets and systematic mechanisms by which GAS protects against AD and MCI remain poorly clarified; target engagement is inferred from computational simulation rather than direct biochemical validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods\/results<\/jats:title>\n                    <jats:p>\n                      This study adopted an integrated approach of network pharmacology, transcriptome-based machine learning, molecular simulation, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      cellular validation to explore the therapeutic mechanisms of GAS against AD\/MCI. A total of 127 overlapping therapeutic targets of GAS, AD, and MCI were identified, which were mainly enriched in synaptic transmission and calcium signaling pathways. Four core hub genes (\n                      <jats:italic>ACHE<\/jats:italic>\n                      ,\n                      <jats:italic>S1PR5<\/jats:italic>\n                      ,\n                      <jats:italic>SERPINE1<\/jats:italic>\n                      , and\n                      <jats:italic>TOP2A<\/jats:italic>\n                      ) were further screened by intersecting candidate targets with AD differentially expressed genes from the GSE329677 dataset. The ensemble Logistic + SVM machine learning model exhibited optimal diagnostic efficiency with an AUC value of 0.897. Molecular docking and 50\u00a0ns molecular dynamics simulations confirmed that GAS stably bound to the four target proteins and maintained stable binding states under physiological conditions. In an A\u03b2\n                      <jats:sub>1-42<\/jats:sub>\n                      oligomer-injured N2a neuronal model, GAS showed no significant cytotoxicity at concentrations ranging from 0.1 to 100\u00a0\u03bcM. Notably, 25\u00a0\u03bcM GAS markedly reversed A\u03b2\n                      <jats:sub>1-42<\/jats:sub>\n                      -induced neuronal death and excessive intracellular ROS accumulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies four novel candidate core therapeutic targets of GAS against AD\/MCI and provides computational evidence for their stable atomic-level binding characteristics. GAS exerts prominent neuroprotective effects through anti-apoptotic and antioxidant mechanisms in A\u03b2-injured neurons. These findings provide a novel theoretical basis and preclinical evidence for the development of GAS as a natural candidate agent for AD intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1937359","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:48:07Z","timestamp":1790660887000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gastrodin alleviates mild cognitive impairment and Alzheimer\u2019s disease via candidate targeting of ACHE, S1PR5, SERPINE1, and TOP2A: an integrative computational and cellular study"],"prefix":"10.3389","volume":"17","author":[{"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Innovation Institute of Integrated Traditional Chinese and Western Medicine, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences","place":["Jinan, China"]},{"name":"Taihe Hospital, Hubei University of Medicine","place":["Shiyan, China"]},{"name":"Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Human Anatomy, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-xi","family":"Liu","sequence":"additional","affiliation":[{"name":"Innovation Institute of Integrated Traditional Chinese and Western Medicine, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-lu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Innovation Institute of Integrated Traditional Chinese and Western Medicine, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-xian","family":"Li","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine (TCM) Rehabilitation Department, Danjiangkou Liuliping Central Health Center","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Human Anatomy, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong-hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Taihe Hospital, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shengli Oilfield Central Hospital","place":["Dongying, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Innovation Institute of Integrated Traditional Chinese and Western Medicine, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"22168","DOI":"10.1038\/s41598-026-50123-y","article-title":"Molecular docking, DFT analysis, pharmacokinetic profiling and MD simulation of ilex aquifolium L. flavonoids as potential \u03b1-glucosidase predicted inhibitors for diabetes","volume":"16","author":"Alnajeebi","year":"2026","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"136836","DOI":"10.1016\/j.foodchem.2023.136836","article-title":"Research advances of molecular docking and molecular dynamic simulation in recognizing interaction between muscle proteins and exogenous additives","volume":"429","author":"Bai","year":"2023","journal-title":"Food Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1007\/s11030-023-10684-w","article-title":"Network pharmacology, molecular docking, and molecular dynamics simulation to elucidate the mechanism of anti-aging action of Tinospora cordifolia","volume":"28","author":"Bisht","year":"2024","journal-title":"Mol. Divers"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7342","DOI":"10.3390\/ijms26157342","article-title":"Investigating neuroprotective effects of berberine on mitochondrial dysfunction and autophagy impairment in Parkinson's disease","volume":"26","author":"Cha","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"13729","DOI":"10.3390\/ijms241813729","article-title":"Establishment of a seven-gene signature associated with CD8(+) T cells through the utilization of both single-cell and bulk RNA-sequencing techniques in clear cell renal cell carcinoma","volume":"24","author":"Chen","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1002\/psp4.12351","article-title":"Quantitative systems pharmacology model for alzheimer disease indicates targeting sphingolipid dysregulation as potential treatment option","volume":"7","author":"Clausznitzer","year":"2018","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.drudis.2021.09.007","article-title":"Machine-learning methods for ligand-protein molecular docking","volume":"27","author":"Crampon","year":"2022","journal-title":"Drug Discov. Today"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5200","DOI":"10.3390\/ijms27125200","article-title":"The role of Sphingosine-1-Phosphate signaling in cerebral ischemia\/reperfusion injury and Alzheimer's disease pathology","volume":"27","author":"Czubowicz","year":"2026","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"113492","DOI":"10.1016\/j.ejmech.2021.113492","article-title":"Dual-target compounds for Alzheimer's disease: natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR)","volume":"221","author":"Ferreira","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"114646","DOI":"10.1016\/j.jep.2021.114646","article-title":"Transcriptome sequencing reveals Gastrodia elata blume could increase the cell viability of eNPCs under hypoxic condition by improving DNA damage repair ability","volume":"282","author":"Gong","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3892\/etm.2021.11091","article-title":"Gastrodin inhibits high glucose-induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK\/Nrf2 signaling pathway","volume":"23","author":"Huang","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s00401-024-02839-2","article-title":"Amyloid-\u03b2 oligomers increase the binding and internalization of tau oligomers in human synapses","volume":"149","author":"Kadamangudi","year":"2024","journal-title":"Acta Neuropathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"100630","DOI":"10.1016\/j.xcrm.2022.100630","article-title":"A\u03b2 oligomer concentration in mouse and human brain and its drug-induced reduction ex vivo","volume":"3","author":"Kass","year":"2022","journal-title":"Cell Rep. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e202500908","DOI":"10.1002\/cphc.202500908","article-title":"A theoretical study of electron attachment to uracil and 5-Halouracil","volume":"27","author":"Kumar","year":"2026","journal-title":"Chemphyschem"},{"key":"B15","doi-asserted-by":"publisher","first-page":"106","DOI":"10.4172\/2324-8769.1000106","article-title":"Novel combinatorial therapeutic targeting of PAI-1 (SERPINE1) gene expression in Alzheimer's disease","volume":"1","author":"Kutz","year":"2012","journal-title":"Mol. Med. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.7326\/m23-1603","article-title":"Clinical effectiveness of cognitively enhanced Tai Ji quan training on global cognition and dual-task performance during walking in older adults with mild cognitive impairment or self-reported memory concerns: a randomized controlled trial","volume":"176","author":"Li","year":"2023","journal-title":"Ann. Intern Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.3390\/foods13152460","article-title":"Gastrodin alleviates DSS-induced colitis in mice through strengthening intestinal barrier and modulating gut microbiota","volume":"13","author":"Li","year":"2024","journal-title":"Foods"},{"key":"B18","doi-asserted-by":"publisher","first-page":"120680","DOI":"10.1016\/j.ecoenv.2026.120680","article-title":"Linking bisphenol a exposure to pancreatic cancer: evidence from population epidemiology, multi-omics screening, and cellular validation","volume":"323","author":"Lin","year":"2026","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"13003","DOI":"10.2147\/CMAR.S279800","article-title":"Resatorvid relieves breast cancer complicated with depression by inactivating hippocampal microglia through TLR4\/NF-kappaB\/NLRP3 signaling pathway","volume":"12","author":"Luo","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"5241449","DOI":"10.1155\/2022\/5241449","article-title":"Treatment combining focused ultrasound with gastrodin alleviates memory deficit and neuropathology in an Alzheimer's disease-like experimental mouse model","volume":"2022","author":"Luo","year":"2022","journal-title":"Neural Plast."},{"key":"B21","doi-asserted-by":"publisher","first-page":"20557","DOI":"10.1038\/s41598-026-59686-2","article-title":"Valorization of Moringa oleifera pericarp via semi-synthetic sugar-based enone derivatives with anticancer potential: phytochemical isolation, cytotoxic evaluation, and dual EGFR\/CAIX targeting","volume":"16","author":"Majed","year":"2026","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"108471","DOI":"10.1016\/j.jmgm.2023.108471","article-title":"Repurposing of FDA-approved drugs as dual-acting MAO-B and AChE inhibitors against Alzheimer's disease: an in silico and in vitro study","volume":"122","author":"Mateev","year":"2023","journal-title":"J. Mol. Graph Model"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e202500053","DOI":"10.1002\/cbic.202500053","article-title":"The evolution of AChE inhibitors in Alzheimer's disease: from single-target to multi-target ligands","volume":"26","author":"Mehta","year":"2025","journal-title":"Chembiochem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"157981","DOI":"10.1016\/j.phymed.2026.157981","article-title":"Scopoletin alleviates cognitive deficits in 5xFAD mice via suppressing microglial inflammatory response","volume":"153","author":"Ouyang","year":"2026","journal-title":"Phytomedicine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"818","DOI":"10.3390\/genes16070818","article-title":"Brain and CSF Alzheimer's biomarkers are associated with SERPINE1 gene expression","volume":"16","author":"Picard","year":"2025","journal-title":"Genes (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s13195-021-00813-8","article-title":"A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-A\u03b2 protofibril antibody","volume":"13","author":"Swanson","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"849994","DOI":"10.3389\/fphar.2022.849994","article-title":"Pharmacodynamics, network pharmacology, and pharmacokinetics of Chinese medicine formula 9002A in the treatment of Alzheimer's disease","volume":"13","author":"Tang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.tips.2024.05.005","article-title":"Multi-target drugs for Alzheimer's disease","volume":"45","author":"Turgutalp","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"155518","DOI":"10.1016\/j.phymed.2024.155518","article-title":"Gastrodin regulates the TLR4\/TRAF6\/NF-\u03baB pathway to reduce neuroinflammation and microglial activation in an AD model","volume":"128","author":"Wang","year":"2024","journal-title":"Phytomedicine"},{"key":"B30","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1111\/rda.13935","article-title":"Measurement of membrane integrity in canine spermatozoa using a fluorescent computer-assisted spermatozoal quantification method after SYBR-14\/PI staining compared with manual counting after CFDA\/PI staining","volume":"56","author":"Watts","year":"2021","journal-title":"Reprod. Domest. Anim."},{"key":"B31","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1007\/s12272-023-01463-0","article-title":"Review on pharmacological effects of gastrodin","volume":"46","author":"Xiao","year":"2023","journal-title":"Arch. Pharm. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"32009","DOI":"10.1038\/s41598-025-16785-w","article-title":"Single cell-RNA sequencing reveal TOP2A as a key driver of hepatocellular carcinoma progression","volume":"15","author":"Xie","year":"2025","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e209820","DOI":"10.1212\/wnl.0000000000209820","article-title":"Association of seizure control with cognition in people with normal cognition and mild cognitive impairment","volume":"103","author":"Zawar","year":"2024","journal-title":"Neurology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"102341","DOI":"10.1016\/j.arr.2024.102341","article-title":"Research progress in Alzheimer's disease and bone-brain axis","volume":"98","author":"Zhang","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"bbad518","DOI":"10.1093\/bib\/bbad518","article-title":"Network pharmacology: towards the artificial intelligence-based precision traditional Chinese medicine","volume":"25","author":"Zhang","year":"2023","journal-title":"Brief. Bioinform"},{"key":"B36","doi-asserted-by":"publisher","first-page":"113012","DOI":"10.1016\/j.intimp.2024.113012","article-title":"Gastrodin against oxidative stress-inflammation crosstalk via inhibiting mtDNA\/TLR9 and JAK2\/STAT3 signaling to ameliorate ischemic stroke injury","volume":"141","author":"Zhang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"16458","DOI":"10.1021\/acs.est.6c00049","article-title":"Mechanistic insights into PET-MPs-Aggravated ischemic stroke via integrated computational-experimental approaches","volume":"60","author":"Zhang","year":"2026","journal-title":"Environ. Sci. Technol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1186\/s12871-022-01915-y","article-title":"Gastrodin improves neuroinflammation-induced cognitive dysfunction in rats by regulating NLRP3 inflammasome","volume":"22","author":"Zheng","year":"2022","journal-title":"BMC Anesthesiol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1186\/s12911-026-03661-4","article-title":"Inflammatory marker-driven deep learning model for postoperative gastric cancer prognosis","author":"Zhu","year":"2026","journal-title":"BMC Med. Inf. Decis. Mak"},{"key":"B40","doi-asserted-by":"publisher","first-page":"6263","DOI":"10.1021\/acs.jpcb.6c00802","article-title":"Investigation of the interactions and pH-Dependent structural changes in helical peptides by molecular dynamics simulations","volume":"130","author":"Zurm\u00fchl","year":"2026","journal-title":"J. Phys. Chem. B"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1937359\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:48:09Z","timestamp":1790660889000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1937359\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":40,"alternative-id":["10.3389\/fphar.2026.1937359"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1937359","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1937359"}}