{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:20:08Z","timestamp":1787750408578,"version":"build-2784847793"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Spinal cord injury (SCI) is a disease that causes significant functional impairment and high mortality, imposing a heavy economic burden on patients and society. In this in-silico study, we investigated the potential therapeutic targets and underlying mechanisms of naringenin (NAR) in SCI by integrating network pharmacology, molecular docking, and molecular dynamics (MD) simulation. The intersection of NAR and SCI targets was used to construct a protein\u2013protein interaction network using the STRING database. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Wiki Pathway enrichment analyses were performed using the DAVID bioinformatics resource. Finally, we used molecular docking and MD simulation to study the binding interactions between NAR and the core targets. The results show that the core targets of NAR for spinal cord injury include estrogen receptor 1, AKT serine\/threonine kinase 1, B-cell lymphoma 2, PPARG, MAPK8, mechanistic target of rapamycin, protein kinase cAMP-activated catalytic subunit alpha, and HRas proto-oncogene, GTPase. These targets and associated biological processes provide multiple mechanisms supporting NAR\u2019s action. In addition, enrichment analysis indicates that the AMPK, FoxO, and PI3K\u2013Akt\u2013mechanistic target of rapamycin signaling pathways, autophagy, and apoptosis are the main pathways through which NAR acts in SCI. Molecular docking results show that the binding energy between NAR and key proteins ranges from \u22127.1 to \u22128.2 kcal\/mol, providing a molecular basis for NAR\u2019s treatment of SCI. Molecular dynamics simulation results indicate that the AKT serine\/threonine kinase 1\u2013NAR and B-cell lymphoma 2\u2013NAR complexes exhibit good stability. In summary, this study systematically predicts the key targets and signaling pathways through which NAR may act in SCI, providing a theoretical basis for future mechanistic and translational research. However, because the findings are based on computational analyses alone, further in vitro and in vivo validation is required.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/md.0000000000049385","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:01:02Z","timestamp":1782108062000},"page":"e49385","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of potential targets and mechanisms of naringenin in the treatment of spinal cord injury: A network pharmacology, molecular docking, and molecular dynamics simulation study"],"prefix":"10.1097","volume":"105","author":[{"given":"A-bing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Spine Surgery, The First Affiliated Hospital of Xinjiang Medical University, \u00dcr\u00fcmqi, Xinjiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1005-9177","authenticated-orcid":false,"given":"Wei-bin","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, The First Affiliated Hospital of Xinjiang Medical University, \u00dcr\u00fcmqi, Xinjiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20260820","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s12916-024-03514-9","article-title":"Global incidence and characteristics of spinal cord injury since 2000-2021: a systematic review and meta-analysis.","volume":"22","author":"Lu","year":"2024","journal-title":"BMC Med"},{"key":"R2-20260820","first-page":"20231","article-title":"Spinal cord injury rehabilitation [Ryggm\u00e4rgsskada \u2013 ett ovanligt tillst\u00e5nd med komplexa behov].","volume":"118","author":"Hill","year":"2021","journal-title":"Lakartidningen"},{"key":"R3-20260820","doi-asserted-by":"crossref","first-page":"949939","DOI":"10.3389\/fncel.2022.949939","article-title":"Pyroptosis in spinal cord injury.","volume":"16","author":"Yin","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"R4-20260820","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.nec.2021.03.002","article-title":"Pathophysiology of spinal cord injury.","volume":"32","author":"Hachem","year":"2021","journal-title":"Neurosurg Clin N Am"},{"key":"R5-20260820","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12974-021-02337-2","article-title":"Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration.","volume":"18","author":"Hellenbrand","year":"2021","journal-title":"J Neuroinflammation"},{"key":"R6-20260820","doi-asserted-by":"crossref","first-page":"3473","DOI":"10.1007\/s11064-023-03993-x","article-title":"Research progress of antioxidants in oxidative stress therapy after spinal cord injury.","volume":"48","author":"Zhang","year":"2023","journal-title":"Neurochem Res"},{"key":"R7-20260820","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1080\/1028415X.2023.2243089","article-title":"Naringenin: its chemistry and roles in neuroprotection.","volume":"27","author":"Atoki","year":"2024","journal-title":"Nutr Neurosci"},{"key":"R8-20260820","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s42003-024-06615-6","article-title":"Naringenin ameliorates amyloid-\u03b2 pathology and neuroinflammation in Alzheimer\u2019s disease.","volume":"7","author":"Zhu","year":"2024","journal-title":"Commun Biol"},{"key":"R9-20260820","doi-asserted-by":"crossref","first-page":"e14415","DOI":"10.1111\/jfbc.14415","article-title":"Naringenin: a prospective therapeutic agent for Alzheimer\u2019s and Parkinson\u2019s disease.","volume":"46","author":"Goyal","year":"2022","journal-title":"J Food Biochem"},{"key":"R10-20260820","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/978-1-0716-3327-4_32","article-title":"Protein-protein interaction network exploration using cytoscape.","volume":"2690","author":"Majeed","year":"2023","journal-title":"Methods Mol Biol"},{"key":"R11-20260820","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/bs.apha.2025.01.007","article-title":"Molecular dynamics simulations: Insights into protein and protein ligand interactions.","volume":"103","author":"Grewal","year":"2025","journal-title":"Adv Pharmacol"},{"key":"R12-20260820","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/978-1-0716-3985-6_6","article-title":"Molecular dynamics simulations in protein-protein docking.","volume":"2780","author":"Cie\u015blak","year":"2024","journal-title":"Methods Mol Biol"},{"key":"R13-20260820","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-1-0716-3441-7_7","article-title":"Applications of molecular dynamics simulations in drug discovery.","volume":"2714","author":"AlRawashdeh","year":"2024","journal-title":"Methods Mol Biol"},{"key":"R14-20260820","doi-asserted-by":"crossref","first-page":"758131","DOI":"10.3389\/fgene.2021.758131","article-title":"Protein function prediction based on PPI networks: network reconstruction vs edge enrichment.","volume":"12","author":"Zhou","year":"2021","journal-title":"Front Genet"},{"key":"R15-20260820","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible.","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"R16-20260820","doi-asserted-by":"crossref","first-page":"e0294236","DOI":"10.1371\/journal.pone.0294236","article-title":"SRplot: a free online platform for data visualization and graphing.","volume":"18","author":"Tang","year":"2023","journal-title":"PLoS One"},{"key":"R17-20260820","doi-asserted-by":"crossref","first-page":"e13275","DOI":"10.1111\/cpr.13275","article-title":"The PI3K\/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: mechanisms and therapeutic opportunities.","volume":"55","author":"He","year":"2022","journal-title":"Cell Prolif"},{"key":"R18-20260820","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1007\/s11033-011-1127-1","article-title":"PI3 Kinase regulation of neural regeneration and muscle hypertrophy after spinal cord injury.","volume":"39","author":"Zhao","year":"2012","journal-title":"Mol Biol Rep"},{"key":"R19-20260820","first-page":"38","article-title":"Bcl-2 in suppressing neuronal apoptosis after spinal cord injury.","volume":"2","author":"Wang","year":"2011","journal-title":"World J Emerg Med"},{"key":"R20-20260820","doi-asserted-by":"crossref","first-page":"105074","DOI":"10.1016\/j.neubiorev.2023.105074","article-title":"The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury.","volume":"146","author":"Shvetcov","year":"2023","journal-title":"Neurosci Biobehav Rev"},{"key":"R21-20260820","doi-asserted-by":"crossref","first-page":"6386729","DOI":"10.1155\/2019\/6386729","article-title":"PPAR-\u03b3 activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome in spinal cord-derived neurons.","volume":"2019","author":"Meng","year":"2019","journal-title":"Mediators Inflamm"},{"key":"R22-20260820","doi-asserted-by":"crossref","first-page":"1701726","DOI":"10.3389\/fphar.2025.1701726","article-title":"Protective effects of naringenin and naringin in organ ischemia\/reperfusion injuries: a comprehensive narrative review.","volume":"16","author":"Hou","year":"2025","journal-title":"Front Pharmacol"},{"key":"R23-20260820","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.gene.2016.07.037","article-title":"Naringenin inhibits spinal cord injury-induced activation of neutrophils through miR-223.","volume":"592","author":"Shi","year":"2016","journal-title":"Gene"},{"key":"R24-20260820","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3344\/kjp.2022.35.3.291","article-title":"Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activities.","volume":"35","author":"Fakhri","year":"2022","journal-title":"Korean J Pain"},{"key":"R25-20260820","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1007\/s12035-020-01969-4","article-title":"Naringenin upregulates AMPK-mediated autophagy to rescue neuronal cells from \u03b2-Amyloid (1-42) evoked neurotoxicity.","volume":"57","author":"Ahsan","year":"2020","journal-title":"Mol Neurobiol"},{"key":"R26-20260820","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1111\/cns.12856","article-title":"AMP-activated protein kinase-dependent induction of autophagy by erythropoietin protects against spinal cord injury in rats.","volume":"24","author":"Wang","year":"2018","journal-title":"CNS Neurosci Ther"},{"key":"R27-20260820","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1007\/s10529-020-02939-5","article-title":"Neuroprotection of melatonin on spinal cord injury by activating autophagy and inhibiting apoptosis via SIRT1\/AMPK signaling pathway.","volume":"42","author":"Gao","year":"2020","journal-title":"Biotechnol Lett"},{"key":"R28-20260820","doi-asserted-by":"crossref","first-page":"134747","DOI":"10.1016\/j.neulet.2020.134747","article-title":"Liraglutide provides neuroprotection by regulating autophagy through the AMPK-FOXO3 signaling pathway in a spinal contusion injury rat model.","volume":"720","author":"Zhang","year":"2020","journal-title":"Neurosci Lett"},{"key":"R29-20260820","doi-asserted-by":"crossref","first-page":"135263","DOI":"10.1016\/j.neulet.2020.135263","article-title":"Zinc promotes autophagy and inhibits apoptosis through AMPK\/mTOR signaling pathway after spinal cord injury.","volume":"736","author":"Lin","year":"2020","journal-title":"Neurosci Lett"},{"key":"R30-20260820","doi-asserted-by":"crossref","first-page":"102145","DOI":"10.1016\/j.jchemneu.2022.102145","article-title":"Ulinastatin attenuates spinal cord injury by targeting AMPK\/NLRP3 signaling pathway.","volume":"125","author":"Guo","year":"2022","journal-title":"J Chem Neuroanat"},{"key":"R31-20260820","doi-asserted-by":"crossref","first-page":"8010670","DOI":"10.1155\/2022\/8010670","article-title":"Sesamol attenuates neuroinflammation by regulating the AMPK\/SIRT1\/NF-\u03baB signaling pathway after spinal cord injury in mice.","volume":"2022","author":"Feng","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"R32-20260820","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41420-023-01780-9","article-title":"FUNDC1-induced mitophagy protects spinal cord neurons against ischemic injury.","volume":"10","author":"Chen","year":"2024","journal-title":"Cell Death Discov"},{"key":"R33-20260820","doi-asserted-by":"crossref","first-page":"e70200","DOI":"10.1111\/cns.70200","article-title":"Vimentin inhibits neuronal apoptosis after spinal cord injury by enhancing autophagy.","volume":"31","author":"Zhao","year":"2025","journal-title":"CNS Neurosci Ther"},{"key":"R34-20260820","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41419-023-06154-8","article-title":"Autophagy: regulator of cell death.","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis"},{"key":"R35-20260820","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41419-020-2724-5","article-title":"Autophagy as a modulator of cell death machinery.","volume":"11","author":"Noguchi","year":"2020","journal-title":"Cell Death Dis"},{"key":"R36-20260820","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/s12276-020-0455-4","article-title":"Autophagy as a decisive process for cell death.","volume":"52","author":"Jung","year":"2020","journal-title":"Exp Mol Med"},{"key":"R37-20260820","doi-asserted-by":"crossref","first-page":"111738","DOI":"10.1016\/j.intimp.2024.111738","article-title":"Fisetin orchestrates neuroinflammation resolution and facilitates spinal cord injury recovery through enhanced autophagy in pro-inflammatory glial cells.","volume":"130","author":"Liu","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"R38-20260820","doi-asserted-by":"crossref","first-page":"761273","DOI":"10.3389\/fcell.2021.761273","article-title":"Biological functions and therapeutic potential of autophagy in spinal cord injury.","volume":"9","author":"Liao","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"R39-20260820","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1167\/iovs.66.11.74","article-title":"Autophagy regulates M\u00fcller Glial cell inflammatory activation.","volume":"66","author":"Doggett","year":"2025","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"R40-20260820","doi-asserted-by":"crossref","first-page":"849","DOI":"10.7150\/thno.74324","article-title":"Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux.","volume":"13","author":"He","year":"2023","journal-title":"Theranostics"},{"key":"R41-20260820","doi-asserted-by":"crossref","first-page":"765","DOI":"10.4103\/1673-5374.295347","article-title":"Exogenous platelet-derived growth factor improves neurovascular unit recovery after spinal cord injury.","volume":"16","author":"Ye","year":"2021","journal-title":"Neural Regen Res"},{"key":"R42-20260820","doi-asserted-by":"crossref","first-page":"828896","DOI":"10.3389\/fphar.2022.828896","article-title":"ALG-bFGF hydrogel inhibiting autophagy contributes to protection of blood-spinal cord barrier integrity via PI3K\/Akt\/FOXO1\/KLF4 pathway after SCI.","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Pharmacol"},{"key":"R43-20260820","doi-asserted-by":"crossref","first-page":"e70543","DOI":"10.1111\/jcmm.70543","article-title":"Felodipine promotes the recovery of mice with spinal cord injury by activating macrolipophagy through the AMPK-mTOR pathway.","volume":"29","author":"Mao","year":"2025","journal-title":"J Cell Mol Med"},{"key":"R44-20260820","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1038\/onc.2008.24","article-title":"FOXOs, cancer and regulation of apoptosis.","volume":"27","author":"Fu","year":"2008","journal-title":"Oncogene"},{"key":"R45-20260820","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.freeradbiomed.2014.07.039","article-title":"FoxO proteins\u2019 nuclear retention and BH3-only protein Bim induction evoke mitochondrial dysfunction-mediated apoptosis in berberine-treated HepG2 cells.","volume":"76","author":"Shukla","year":"2014","journal-title":"Free Radic Biol Med"},{"key":"R46-20260820","doi-asserted-by":"crossref","first-page":"e22760","DOI":"10.1096\/fj.202200962RRRR","article-title":"miR-872-5p\/FOXO3a\/Wnt signaling feed-forward loop promotes proliferation of endogenous neural stem cells after spinal cord ischemia-reperfusion injury in rats.","volume":"37","author":"Li","year":"2023","journal-title":"FASEB J"},{"key":"R47-20260820","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/jcb.24371","article-title":"FOXO3a\/p27kip1 expression and essential role after acute spinal cord injury in adult rat.","volume":"114","author":"Zhang","year":"2013","journal-title":"J Cell Biochem"},{"key":"R48-20260820","doi-asserted-by":"crossref","first-page":"110832","DOI":"10.1016\/j.brainresbull.2023.110832","article-title":"Temporal profiling and validation of oxidative stress-related genes in spinal cord injury.","volume":"205","author":"Liu","year":"2023","journal-title":"Brain Res Bull"},{"key":"R49-20260820","doi-asserted-by":"crossref","first-page":"113881","DOI":"10.1016\/j.biopha.2022.113881","article-title":"The role of PI3K\/Akt signalling pathway in spinal cord injury.","volume":"156","author":"Xiao","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"R50-20260820","first-page":"2832","article-title":"The PI3K\/Akt\/FOXO3a pathway regulates regeneration following spinal cord injury in adult rats through TNF-\u03b1 and p27kip1 expression.","volume":"41","author":"Lu","year":"2018","journal-title":"Int J Mol Med"},{"key":"R51-20260820","doi-asserted-by":"crossref","first-page":"6","DOI":"10.21037\/atm-21-5561","article-title":"The decreased expression of miR-429 in plasma exosomes after spinal cord injury inhibits neuronal apoptosis by mediating the PTEN\/PI3K\/Akt pathway.","volume":"10","author":"Huang","year":"2022","journal-title":"Ann Transl Med"},{"key":"R52-20260820","doi-asserted-by":"crossref","first-page":"114739","DOI":"10.1016\/j.expneurol.2024.114739","article-title":"AAV-mediated VEGFA overexpression promotes angiogenesis and recovery of locomotor function following spinal cord injury via PI3K\/Akt signaling.","volume":"375","author":"Miao","year":"2024","journal-title":"Exp Neurol"},{"key":"R53-20260820","doi-asserted-by":"crossref","first-page":"110399","DOI":"10.1016\/j.abb.2025.110399","article-title":"UCP2 attenuates neural apoptosis and inflammation in spinal cord injury by inducing the acetylation of ANXA1 and activating the PI3K\/AKT pathway.","volume":"768","author":"Zhu","year":"2025","journal-title":"Arch Biochem Biophys"},{"key":"R54-20260820","doi-asserted-by":"crossref","first-page":"117642","DOI":"10.1016\/j.lfs.2020.117642","article-title":"Ginsenoside Rg1-induced activation of astrocytes promotes functional recovery via the PI3K\/Akt signaling pathway following spinal cord injury.","volume":"252","author":"Xu","year":"2020","journal-title":"Life Sci"},{"key":"R55-20260820","doi-asserted-by":"crossref","first-page":"10830","DOI":"10.1007\/s12035-024-04248-8","article-title":"Transplantation of Wnt5a-modified bone marrow mesenchymal stem cells promotes recovery after spinal cord injury via the PI3K\/AKT pathway.","volume":"61","author":"Yang","year":"2024","journal-title":"Mol Neurobiol"},{"key":"R56-20260820","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.expneurol.2016.01.023","article-title":"The role of the PI3K\/Akt\/mTOR pathway in glial scar formation following spinal cord injury.","volume":"278","author":"Chen","year":"2016","journal-title":"Exp Neurol"},{"key":"R57-20260820","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1089\/neu.2020.7413","article-title":"Blood-spinal cord barrier in spinal cord injury: a review.","volume":"38","author":"Jin","year":"2021","journal-title":"J Neurotrauma"}],"container-title":["Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/MD.0000000000049385","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:33:03Z","timestamp":1787747583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/MD.0000000000049385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":57,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/md.0000000000049385","relation":{},"ISSN":["0025-7974","1536-5964"],"issn-type":[{"value":"0025-7974","type":"print"},{"value":"1536-5964","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"assertion":[{"value":"2025-10-24","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-03","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}