{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:04:11Z","timestamp":1785434651268,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003995","name":"Anhui Provincial Natural Science Foundation","doi-asserted-by":"crossref","award":["2308085MC76"],"award-info":[{"award-number":["2308085MC76"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["12375352"],"award-info":[{"award-number":["12375352"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["12375352"],"award-info":[{"award-number":["12375352"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2025M770911"],"award-info":[{"award-number":["2025M770911"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2025M770911"],"award-info":[{"award-number":["2025M770911"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by \u03b2-amyloid (A\u03b2) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD+\/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in A\u03b242-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality.<\/jats:p>","DOI":"10.3390\/ijms27135708","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:48:16Z","timestamp":1782366496000},"page":"5708","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vitamin K2 Promotes Mitochondrial Structural and Functional Homeostasis to Ameliorate Alzheimer Pathology by Targeting the EGFR-Ras-ERK Signaling Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Yanan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhong","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asante Obed","family":"Frimpong","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biguo","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manman","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China"},{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-1737","authenticated-orcid":false,"given":"Changsheng","family":"Shao","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40035-021-00270-1","article-title":"The Role of Pathological Tau in Synaptic Dysfunction in Alzheimer\u2019s Diseases","volume":"10","author":"Wu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1002\/alz.13015","article-title":"Impact of Alzheimer\u2019s Association Support and Engagement in the AD\/ADRD Research Community through the COVID-19 Pandemic and Beyond","volume":"19","author":"Meyers","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/j.jalz.2018.01.010","article-title":"CSF Biomarkers of Alzheimer\u2019s Disease Concord with Amyloid-\u03b2 PETand Predict Clinical Progression: A Study of Fully Automated Immunoassays in BioFINDER and ADNI Cohorts","volume":"14","author":"Hansson","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.2174\/1570159X18666200528142429","article-title":"Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer\u2019s Disease","volume":"18","author":"Khan","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.neuron.2011.06.003","article-title":"Mitochondria: The next (Neurode)Generation","volume":"70","author":"Schon","year":"2011","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.tcb.2014.11.002","article-title":"Protecting the Mitochondrial Powerhouse","volume":"25","author":"Fang","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chakravorty, A., Jetto, C.T., and Manjithaya, R. (2019). Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer\u2019s Disease Pathogenesis. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00311"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108354","DOI":"10.1016\/j.neuropharm.2020.108354","article-title":"9R, the Cholinesterase and Amyloid Beta Aggregation Dual Inhibitor, as a Multifunctional Agent to Improve Cognitive Deficit and Neuropathology in the Triple-Transgenic Alzheimer\u2019s Disease Mouse Model","volume":"181","author":"Ju","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104665","DOI":"10.1016\/j.ebiom.2023.104665","article-title":"Safety, Tolerability, Immunogenicity, and Efficacy of UB-311 in Participants with Mild Alzheimer\u2019s Disease: A Randomised, Double-Blind, Placebo-Controlled, Phase 2a Study","volume":"94","author":"Yu","year":"2023","journal-title":"eBioMedicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.ymthe.2024.03.024","article-title":"APOE2 Gene Therapy Reduces Amyloid Deposition and Improves Markers of Neuroinflammation and Neurodegeneration in a Mouse Model of Alzheimer Disease","volume":"32","author":"Jackson","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1021\/acs.jafc.2c05632","article-title":"A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK\/SIRT1 Pathway in Type 2 Diabetic Osteoporosis","volume":"71","author":"Jin","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Popescu, A., and German, M. (2021). Vitamin K2 Holds Promise for Alzheimer\u2019s Prevention and Treatment. Nutrients, 13.","DOI":"10.3390\/nu13072206"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/biof.1004","article-title":"Vitamin K, an Emerging Nutrient in Brain Function","volume":"38","author":"Ferland","year":"2012","journal-title":"BioFactors"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Saputra, W.D., Aoyama, N., Komai, M., and Shirakawa, H. (2019). Menaquinone-4 Suppresses Lipopolysaccharide-Induced Inflammation in MG6 Mouse Microglia-Derived Cells by Inhibiting the NF-\u03baB Signaling Pathway. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092317"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network Pharmacology: The next Paradigm in Drug Discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chakraborty, R., Vepuri, V., Mhatre, S.D., Paddock, B.E., Miller, S., Michelson, S.J., Delvadia, R., Desai, A., Vinokur, M., and Melicharek, D.J. (2011). Characterization of a Drosophila Alzheimer\u2019s Disease Model: Pharmacological Rescue of Cognitive Defects. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020799"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a009944","DOI":"10.1101\/cshperspect.a009944","article-title":"Drosophila as a Model to Study Mitochondrial Dysfunction in Parkinson\u2019s Disease","volume":"2","author":"Guo","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8690","DOI":"10.1016\/j.biomaterials.2013.07.100","article-title":"Epidermal Growth Factor Receptor Targeting in Cancer: A Review of Trends and Strategies","volume":"34","author":"Yewale","year":"2013","journal-title":"Biomaterials"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D1516","DOI":"10.1093\/nar\/gkae1059","article-title":"PubChem 2025 Update","volume":"53","author":"Kim","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"W609","DOI":"10.1093\/nar\/gkq300","article-title":"PharmMapper Server: A Web Server for Potential Drug Target Identification Using Pharmacophore Mapping Approach","volume":"38","author":"Liu","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1093\/bioinformatics\/btq430","article-title":"Cytoscape Web: An Interactive Web-Based Network Browser","volume":"26","author":"Lopes","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1523\/JNEUROSCI.3699-09.2010","article-title":"Expression of \u03b2-Amyloid Induced Age-Dependent Presynaptic and Axonal Changes in Drosophila","volume":"30","author":"Zhao","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9090","DOI":"10.1523\/JNEUROSCI.1357-09.2009","article-title":"Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer\u2019s Disease","volume":"29","author":"Wang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"fcad356","DOI":"10.1093\/braincomms\/fcad356","article-title":"Role of Oxidative Stress in Neurodegenerative Disorders: A Review of Reactive Oxygen Species and Prevention by Antioxidants","volume":"6","author":"Houldsworth","year":"2024","journal-title":"Brain Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1083\/jcb.201803152","article-title":"Fueling Thought: Management of Glycolysis and Oxidative Phosphorylation in Neuronal Metabolism","volume":"217","author":"Yellen","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.apsb.2021.11.003","article-title":"Mitochondrial Complex I as a Therapeutic Target for Alzheimer\u2019s Disease","volume":"12","author":"Trushina","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/157015909787602823","article-title":"Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options","volume":"7","author":"Uttara","year":"2009","journal-title":"Curr. Neuropharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eabo3610","DOI":"10.1126\/sciadv.abo3610","article-title":"Targeted BACE-1 Inhibition in Microglia Enhances Amyloid Clearance and Improved Cognitive Performance","volume":"8","author":"Singh","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/1750-1326-8-35","article-title":"Drosophila Melanogaster as a Model Organism for Alzheimer\u2019s Disease","volume":"8","author":"Voigt","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175875","DOI":"10.1016\/j.ejphar.2023.175875","article-title":"Lapatinib Ditosylate Rescues Motor Deficits in Rotenone-Intoxicated Rats: Potential Repurposing of Anti-Cancer Drug as a Disease-Modifying Agent in Parkinson\u2019s Disease","volume":"954","author":"Mansour","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1126\/science.1218632","article-title":"Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency","volume":"336","author":"Vos","year":"2012","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1016\/j.cub.2022.07.003","article-title":"EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and \u03b2-oxidation","volume":"32","author":"Zhang","year":"2022","journal-title":"Curr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41398-023-02504-4","article-title":"Novel Effects of Ras-MAPK Pathogenic Variants on the Developing Human Brain and Their Link to Gene Expression and Inhibition Abilities","volume":"13","author":"Rai","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm2438","article-title":"Ras Oncogenes: Split Personalities","volume":"9","author":"Karnoub","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1038\/s41388-018-0582-8","article-title":"The ERK2 and JNK Pathways in the Regulation of Metabolic Reprogramming","volume":"38","author":"Papa","year":"2019","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.2147\/DDDT.S503930","article-title":"MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells","volume":"19","author":"Ding","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2174\/1389201011314030002","article-title":"Regulation of Glycolytic and Mitochondrial Metabolism by Ras","volume":"14","author":"Chesney","year":"2013","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/1028415X.2018.1504428","article-title":"Vitamin K2 Protects PC12 Cells against A\u03b2 (1-42) and H2O2-Induced Apoptosis via P38 MAP Kinase Pathway","volume":"23","author":"Hadipour","year":"2020","journal-title":"Nutr. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5708\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:00:30Z","timestamp":1782536430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5708"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":38,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135708"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135708","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]}}}