{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T23:24:32Z","timestamp":1787181872178,"version":"build-2736575974"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":75,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-55411-1","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T22:52:48Z","timestamp":1780699968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gadd45\u03b1 silencing alleviates cerebral ischemia\u2013reperfusion injury by suppressing FOXO1 signaling"],"prefix":"10.1038","volume":"16","author":[{"given":"Cong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"55411_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2025.112127","volume":"229","author":"A Cercel","year":"2026","unstructured":"Cercel, A. et al. Ischemic stroke and comorbidities: Impact on recovery and the role of genetics and epigenetics. Mech. Ageing Dev. 229, 112127 (2026).","journal-title":"Mech. Ageing Dev."},{"key":"55411_CR2","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1016\/S0140-6736(24)00933-4","volume":"403","author":"GBD 2021 Risk Factors Collaborators","year":"2024","unstructured":"GBD 2021 Risk Factors Collaborators. Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 403, 2162\u20132203 (2024).","journal-title":"Lancet"},{"key":"55411_CR3","doi-asserted-by":"publisher","DOI":"10.1177\/26331055241292600","volume":"19","author":"D Majumder","year":"2024","unstructured":"Majumder, D. Ischemic stroke: Pathophysiology and evolving treatment approaches. Neurosci. Insights 19, 26331055241292600 (2024).","journal-title":"Neurosci. Insights"},{"key":"55411_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/biom14030305","volume":"14","author":"MA Salaudeen","year":"2024","unstructured":"Salaudeen, M. A., Bello, N., Danraka, R. N. & Ammani, M. L. Understanding the pathophysiology of ischemic stroke: The basis of current therapies and opportunity for new ones. Biomolecules 14, 305 (2024).","journal-title":"Biomolecules"},{"key":"55411_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01688-x","volume":"9","author":"M Zhang","year":"2024","unstructured":"Zhang, M. et al. Ischemia-reperfusion injury: Molecular mechanisms and therapeutic targets. Signal Transduct. Target. Ther. 9, 12 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"55411_CR6","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/978-3-030-94804-7_9","volume":"1360","author":"FA Sultan","year":"2022","unstructured":"Sultan, F. A. & Sawaya, B. E. Gadd45 in neuronal development, function, and injury. Adv. Exp. Med. Biol. 1360, 117\u2013148 (2022).","journal-title":"Adv. Exp. Med. Biol."},{"key":"55411_CR7","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1349409","volume":"18","author":"M Huang","year":"2024","unstructured":"Huang, M., Wang, J., Liu, W. & Zhou, H. Advances in the role of the GADD45 family in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Front. Neurosci. 18, 1349409 (2024).","journal-title":"Front. Neurosci."},{"key":"55411_CR8","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1002\/med.22015","volume":"44","author":"X Palomer","year":"2024","unstructured":"Palomer, X. et al. GADD45A: With or without you. Med. Res. Rev. 44, 1375\u20131403 (2024).","journal-title":"Med. Res. Rev."},{"key":"55411_CR9","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1007\/s10522-025-10277-0","volume":"26","author":"I Kazmi","year":"2025","unstructured":"Kazmi, I. et al. Translational potential of GADD45\u03b1: biomarker and therapeutic target in age-associated neurodegeneration and longevity. Biogerontology 26, 135 (2025).","journal-title":"Biogerontology"},{"key":"55411_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4614-8289-5_1","volume":"793","author":"JM Salvador","year":"2013","unstructured":"Salvador, J. M., Brown-Clay, J. D. & Fornace, A. J., Jr. Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv. Exp. Med. Biol. 793, 1\u201319 (2013).","journal-title":"Adv. Exp. Med. Biol."},{"key":"55411_CR11","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1042\/BCJ20210777","volume":"479","author":"Z Cheng","year":"2022","unstructured":"Cheng, Z. FoxO transcription factors in mitochondrial homeostasis. Biochem. J. 479, 525\u2013536 (2022).","journal-title":"Biochem. J."},{"key":"55411_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911877","volume":"23","author":"ME Kim","year":"2022","unstructured":"Kim, M. E., Kim, D. H. & Lee, J. S. FoxO transcription factors: Applicability as a novel immune cell regulators and therapeutic targets in oxidative stress-related diseases. Int. J. Mol. Sci. 23, 11877 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"55411_CR13","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41580-023-00649-0","volume":"25","author":"MJ Rodriguez-Colman","year":"2024","unstructured":"Rodriguez-Colman, M. J., Dansen, T. B. & Burgering, B. M. T. FOXO transcription factors as mediators of stress adaptation. Nat. Rev. Mol. Cell Biol. 25, 46\u201364 (2024).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"55411_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06177-1","volume":"14","author":"BF Santos","year":"2023","unstructured":"Santos, B. F., Grenho, I., Martel, P. J., Ferreira, B. I. & Link, W. FOXO family isoforms. Cell Death Dis. 14, 702 (2023).","journal-title":"Cell Death Dis."},{"key":"55411_CR15","doi-asserted-by":"publisher","first-page":"E11731","DOI":"10.1073\/pnas.1814052115","volume":"115","author":"X Du","year":"2018","unstructured":"Du, X. et al. CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1. Proc. Natl. Acad. Sci. USA 115, E11731\u2013E11740 (2018).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"55411_CR16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41573-020-0088-2","volume":"20","author":"G Calissi","year":"2021","unstructured":"Calissi, G., Lam, E. W. & Link, W. Therapeutic strategies targeting FOXO transcription factors. Nat. Rev. Drug Discov. 20, 21\u201338 (2021).","journal-title":"Nat. Rev. Drug Discov."},{"key":"55411_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50393-y","volume":"15","author":"Y Maejima","year":"2024","unstructured":"Maejima, Y. et al. Mst1-mediated phosphorylation of FoxO1 and C\/EBP-\u03b2 stimulates cell-protective mechanisms in cardiomyocytes. Nat. Commun. 15, 6279 (2024).","journal-title":"Nat. Commun."},{"key":"55411_CR18","doi-asserted-by":"publisher","first-page":"11727","DOI":"10.18632\/aging.202866","volume":"13","author":"W Li","year":"2021","unstructured":"Li, W., Zhu, Q., Xu, X. & Hu, X. MiR-27a-3p suppresses cerebral ischemia-reperfusion injury by targeting FOXO1. Aging (Albany NY) 13, 11727\u201311737 (2021).","journal-title":"Aging (Albany NY)"},{"key":"55411_CR19","doi-asserted-by":"publisher","first-page":"242","DOI":"10.12688\/f1000research.51752.2","volume":"10","author":"M Trotman-Lucas","year":"2021","unstructured":"Trotman-Lucas, M. & Gibson, C. L. A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model. F1000Res 10, 242 (2021).","journal-title":"F1000Res"},{"key":"55411_CR20","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1177\/0271678X251352691","volume":"45","author":"C Lim","year":"2025","unstructured":"Lim, C. et al. Assessing the effects of aging on the Koizumi\u2019s and Zea Longa\u2019s methods and their suitability as mouse models for evaluating neurodegeneration post-ischemic stroke: A comparative study. J. Cereb. Blood Flow Metab. 45, 2189\u20132202 (2025).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"55411_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2024.102131","volume":"35","author":"P Cepparulo","year":"2024","unstructured":"Cepparulo, P. et al. Anti-miRNA103\/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage. Mol. Ther. Nucleic Acids 35, 102131 (2024).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"55411_CR22","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj8658","volume":"8","author":"Y Xia","year":"2022","unstructured":"Xia, Y. et al. Neuronal C\/EBP\u03b2\/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression. Sci. Adv. 8, eabj8658 (2022).","journal-title":"Sci. Adv."},{"key":"55411_CR23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1002\/kjm2.12136","volume":"36","author":"JJ Hu","year":"2020","unstructured":"Hu, J. J. et al. miR-15a regulates oxygen glucose deprivation\/reperfusion (OGD\/R)-induced neuronal injury by targeting BDNF. Kaohsiung J. Med. Sci. 36, 27\u201334 (2020).","journal-title":"Kaohsiung J Med Sci."},{"key":"55411_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2024.107413","volume":"156","author":"VA Awasthi","year":"2024","unstructured":"Awasthi, V. A., Dhankar, V. & Singh, S. Novel therapeutic targets for reperfusion injury in ischemic stroke: Understanding the role of mitochondria, excitotoxicity and ferroptosis. Vasc. Pharmacol. 156, 107413 (2024).","journal-title":"Vasc. Pharmacol."},{"key":"55411_CR25","doi-asserted-by":"publisher","first-page":"33618","DOI":"10.1021\/acsami.5c05882","volume":"17","author":"Y Guo","year":"2025","unstructured":"Guo, Y. et al. A carrier-free triple-drug co-assembled nanoformulation for synergistic treatment of cerebral ischemia-reperfusion injury. ACS Appl. Mater. Interfaces 17, 33618\u201333632 (2025).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"55411_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.crneur.2022.100031","volume":"3","author":"DVC Brito","year":"2022","unstructured":"Brito, D. V. C., Kupke, J., Gulmez Karaca, K. & Oliveira, A. M. M. Regulation of neuronal plasticity by the DNA repair associated Gadd45 proteins. Curr. Res. Neurobiol. 3, 100031 (2022).","journal-title":"Curr. Res. Neurobiol."},{"issue":"1","key":"55411_CR27","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1007\/s12035-025-05295-5","volume":"63","author":"J Li","year":"2025","unstructured":"Li, J. et al. DeSUMOylation of spastin enhances AMPA receptor recycling and synaptic plasticity via IST1-dependent endosomal sorting. Mol. Neurobiol. 63, 178 (2025).","journal-title":"Mol. Neurobiol."},{"key":"55411_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112233","volume":"42","author":"H Lu","year":"2023","unstructured":"Lu, H. et al. Synaptotagmin-3 interactions with GluA2 mediate brain damage and impair functional recovery in stroke. Cell Rep. 42, 112233 (2023).","journal-title":"Cell Rep."},{"key":"55411_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2025.110624","volume":"279","author":"CA Chapman","year":"2025","unstructured":"Chapman, C. A., Povysheva, N., Johnson, J. W. & Jacob, T. C. Increased NMDAR activity and GluN2A-NMDAR silent synapse expansion induced by chronic benzodiazepine treatment. Neuropharmacology 279, 110624 (2025).","journal-title":"Neuropharmacology"},{"key":"55411_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2020.111314","volume":"117","author":"R He","year":"2020","unstructured":"He, R., Jiang, Y., Shi, Y., Liang, J. & Zhao, L. Curcumin-laden exosomes target ischemic brain tissue and alleviate cerebral ischemia-reperfusion injury by inhibiting ROS-mediated mitochondrial apoptosis. Mater. Sci. Eng. C Mater. Biol. Appl. 117, 111314 (2020).","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"55411_CR31","doi-asserted-by":"publisher","first-page":"3525","DOI":"10.1007\/s11064-022-03697-8","volume":"47","author":"Q Zhang","year":"2022","unstructured":"Zhang, Q., Jia, M., Wang, Y., Wang, Q. & Wu, J. Cell death mechanisms in cerebral ischemia-reperfusion injury. Neurochem. Res. 47, 3525\u20133542 (2022).","journal-title":"Neurochem. Res."},{"key":"55411_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.00028","volume":"13","author":"L Wu","year":"2020","unstructured":"Wu, L. et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front. Mol. Neurosci. 13, 28 (2020).","journal-title":"Front. Mol. Neurosci."},{"key":"55411_CR33","first-page":"23","volume":"10","author":"TF Beckhauser","year":"2016","unstructured":"Beckhauser, T. F., Francis-Oliveira, J. & De Pasquale, R. Reactive oxygen species: Physiological and physiopathological effects on synaptic plasticity. J. Exp. Neurosci. 10, 23\u201348 (2016).","journal-title":"J. Exp. Neurosci."},{"key":"55411_CR34","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25042030","volume":"25","author":"D Andr\u00e9-L\u00e9vigne","year":"2024","unstructured":"Andr\u00e9-L\u00e9vigne, D. et al. Role of oxygen and its radicals in peripheral nerve regeneration: From hypoxia to physoxia to hyperoxia. Int. J. Mol. Sci. 25, 2030 (2024).","journal-title":"Int. J. Mol. Sci."},{"key":"55411_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01064-1","volume":"7","author":"C Qin","year":"2022","unstructured":"Qin, C. et al. Signaling pathways involved in ischemic stroke: Molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther. 7, 215 (2022).","journal-title":"Signal Transduct. Target. Ther."},{"key":"55411_CR36","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.freeradbiomed.2025.08.049","volume":"240","author":"R Zhou","year":"2025","unstructured":"Zhou, R. et al. Mechanism of lidocaine-induced ROS generation triggering DNA double-strand breaks and promoting intervertebral disc cell senescence via the MYC-DUSP1-P53 axis. Free Radic. Biol. Med. 240, 457\u2013471 (2025).","journal-title":"Free Radic. Biol. Med."},{"key":"55411_CR37","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081853","volume":"9","author":"R Aleksandrov","year":"2020","unstructured":"Aleksandrov, R., Hristova, R., Stoynov, S. & Gospodinov, A. The chromatin response to double-strand DNA breaks and their repair. Cells 9, 1853 (2020).","journal-title":"Cells"},{"key":"55411_CR38","doi-asserted-by":"publisher","DOI":"10.3390\/biom10040570","volume":"10","author":"A Gonz\u00e1lez-Maga\u00f1a","year":"2020","unstructured":"Gonz\u00e1lez-Maga\u00f1a, A. & Blanco, F. J. Human PCNA structure, function and interactions. Biomolecules 10, 570 (2020).","journal-title":"Biomolecules"},{"key":"55411_CR39","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1146\/annurev-genet-021920-092410","volume":"54","author":"B Bonilla","year":"2020","unstructured":"Bonilla, B., Hengel, S. R., Grundy, M. K. & Bernstein, K. A. RAD51 gene family structure and function. Annu. Rev. Genet. 54, 25\u201346 (2020).","journal-title":"Annu. Rev. Genet."},{"key":"55411_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.108451","volume":"301","author":"A Naatz","year":"2025","unstructured":"Naatz, A. et al. Role of SIRT3 in the regulation of Gadd45\u03b1 expression and DNA repair in \u03b2-cells. J. Biol. Chem. 301, 108451 (2025).","journal-title":"J. Biol. Chem."},{"key":"55411_CR41","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.2147\/DDDT.S305016","volume":"15","author":"X Zhang","year":"2021","unstructured":"Zhang, X., Jiang, L. & Liu, H. Forkhead box protein O1: Functional diversity and post-translational modification, a new therapeutic target?. Drug Des. Devel. Ther. 15, 1851\u20131860 (2021).","journal-title":"Drug Des. Devel. Ther."},{"key":"55411_CR42","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01506-x","volume":"9","author":"N Liu","year":"2023","unstructured":"Liu, N. et al. The inhibition of FKBP5 protects \u03b2-cell survival under inflammation stress via AKT\/FOXO1 signaling. Cell Death Discov. 9, 247 (2023).","journal-title":"Cell Death Discov."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55411-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55411-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55411-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T22:44:11Z","timestamp":1787179451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55411-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,6]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["55411"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-55411-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,6]]},"assertion":[{"value":"25 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"26076"}}