{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:06:32Z","timestamp":1790057192545,"version":"4.0.1"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Ischemic stroke is a leading cause of mortality and long-term disability worldwide, yet its underlying molecular mechanisms remain incompletely understood. The pathology involves complex interactions between vascular injury, immune dysregulation, metabolic imbalance, and mitochondrial dysfunction. Traditional single-gene or single-dataset approaches have limitations in capturing the multifactorial nature of the disease. We developed a comprehensive systems-level bioinformatics framework integrating five publicly available transcriptomic datasets (GSE119121, GSE146882, GSE22255, GSE37587, GSE58294). Differential expression analysis, protein-protein interaction network construction, functional enrichment analysis, gene-drug interaction mapping, and molecular docking simulations were performed. Eight core genes were identified through multi-dataset integration. Experimental validation was conducted using a transient middle cerebral artery occlusion (MCAO) rat model, with resveratrol treatment at 10\u00a0mg\/kg and 30\u00a0mg\/kg. qPCR, Western blot, TTC staining, H&amp;amp;E, NIR-II imaging, MRI, and neurological deficit assessments were performed. Integrated analysis identified eight core genes (\n                    <jats:italic>SPTBN1<\/jats:italic>\n                    ,\n                    <jats:italic>ARHGAP39<\/jats:italic>\n                    ,\n                    <jats:italic>ANKRD44<\/jats:italic>\n                    ,\n                    <jats:italic>FBXL19<\/jats:italic>\n                    ,\n                    <jats:italic>FAM171B<\/jats:italic>\n                    ,\n                    <jats:italic>SNORD77<\/jats:italic>\n                    ,\n                    <jats:italic>FITM2<\/jats:italic>\n                    ,\n                    <jats:italic>FIBIN<\/jats:italic>\n                    ) consistently dysregulated across datasets, showing strong associations with neuroinflammation, mitochondrial dysfunction, lipid metabolism, and immune regulation. In the MCAO model, all eight genes were significantly dysregulated at 24\u00a0h post-ischemia. Resveratrol treatment (30\u00a0mg\/kg) normalized expression by 50%\u201360% for all genes (\n                    <jats:italic>SPTBN1<\/jats:italic>\n                    : from 3.2-fold to 1.5-fold;\n                    <jats:italic>ARHGAP39<\/jats:italic>\n                    : from 2.8-fold to 1.3-fold;\n                    <jats:italic>FAM171B<\/jats:italic>\n                    : from 3.5-fold to 1.6-fold;\n                    <jats:italic>SNORD77<\/jats:italic>\n                    : from 0.4-fold to 0.8-fold; all p &amp;lt; 0.01). Resveratrol reduced infarct volume by 52%, improved neurological scores by 60%, suppressed microglial activation\n                    <jats:italic>(Iba-1<\/jats:italic>\n                    intensity reduced by 45.2%, p &amp;lt; 0.01), preserved mitochondrial membrane potential (108% improvement, p &amp;lt; 0.01), and reduced apoptotic cell death. Molecular docking revealed strong binding affinity between resveratrol and target proteins (\n                    <jats:italic>FITM2<\/jats:italic>\n                    : \u22128.2\u00a0kcal\/mol). This study identifies a novel eight-gene signature associated with ischemic stroke and demonstrates that resveratrol effectively modulates these genes through coordinated regulation of neuroinflammation, mitochondrial function, apoptosis, and metabolic pathways. The multi-target therapeutic profile of resveratrol, validated through both computational and experimental approaches, positions it as a promising candidate for ischemic stroke therapy. The systems-level framework established here provides a robust foundation for future biomarker development and therapeutic discovery in complex neurological disorders.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1893306","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:40:53Z","timestamp":1790055653000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems-level analysis uncovers eight hub genes and a resveratrol-based therapeutic strategy for ischemic stroke"],"prefix":"10.3389","volume":"17","author":[{"given":"Sanjeev","family":"Nirala","sequence":"first","affiliation":[{"name":"Gaozhou People\u2019s Hospital","place":["Gaozhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep Kumar","family":"Shah","sequence":"additional","affiliation":[{"name":"Shankar Hospital","place":["Jhapa, Nepal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1186\/s13287-015-0175-1","article-title":"Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke","volume":"6","author":"Abeysinghe","year":"2015","journal-title":"Stem Cell Res. and Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.freeradbiomed.2005.08.044","article-title":"Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia","volume":"40","author":"Adibhatla","year":"2006","journal-title":"Free Radic. 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