{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T15:01:44Z","timestamp":1794409304019,"version":"4.9.0"},"reference-count":144,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemic stroke accounts for approximately 80\u201385% of all stroke cases and triggers a complex cascade of metabolic, immunological, and neurodegenerative processes. Among the key mediators involved, TNF-\u03b1 occupies a central position due to its distinctly dual and phase-dependent actions. Importantly, the biological effects of TNF-\u03b1 are not static but evolve dynamically over time following ischemic insult. During the acute phase of ischemia, a rapid increase in TNF-\u03b1 levels, primarily originating from activated microglia, leads to the predominant activation of the TNFR1 receptor. This results in enhanced apoptosis and necroptosis, disruption of the blood\u2013brain barrier, increased leukocyte recruitment, and the progression of secondary neuronal injury. In later phases, the role of TNF-\u03b1 shifts, with signaling through TNFR2 becoming more prominent, thereby supporting reparative mechanisms, including neurogenesis, angiogenesis, and synaptic remodeling. The dual nature of TNF-\u03b1 means that both its excessive activation and complete inhibition may produce detrimental effects. Notably, the therapeutic relevance of TNF-\u03b1 critically depends on the timing of intervention relative to stroke onset. A comprehensive analysis of current evidence underscores the central, temporally and contextually dependent role of TNF-\u03b1 in the pathophysiology of ischemic stroke. It also indicates that future therapeutic strategies should aim to selectively suppress the harmful TNFR1-mediated signaling while preserving or enhancing TNFR2-dependent neuroprotective pathways. Such time-sensitive and receptor-selective modulation holds promise for limiting acute ischemic injury and promoting endogenous repair processes, representing a compelling direction for the development of next-generation neuroprotective therapies.<\/jats:p>","DOI":"10.3390\/ijms27031424","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T17:38:34Z","timestamp":1769794714000},"page":"1424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Role of TNF-\u03b1 in Ischemic Stroke"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7277-721X","authenticated-orcid":false,"given":"Renata","family":"Ko\u0142odziejska","sequence":"first","affiliation":[{"name":"Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Pawluk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2015-7510","authenticated-orcid":false,"given":"Agnieszka","family":"Tafelska-Kaczmarek","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University in Toru\u0144, Gagarina 7, 87-100 Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Pawluk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Koper","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Oncology Center, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Romanowskiej Street 2, 85-796 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoni","family":"Godlewski","sequence":"additional","affiliation":[{"name":"Student Scientific Club of Biochemistry and Bioorganic Chemistry, Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kuk","sequence":"additional","affiliation":[{"name":"Student Scientific Club of Biochemistry and Bioorganic Chemistry, Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5415-6050","authenticated-orcid":false,"given":"Krzysztof","family":"Sergot","sequence":"additional","affiliation":[{"name":"Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4669-1092","authenticated-orcid":false,"given":"Natalia","family":"Kurhaluk","sequence":"additional","affiliation":[{"name":"Institute of Biology, Pomeranian University in S\u0142upsk, 76-200 S\u0142upsk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4492-4796","authenticated-orcid":false,"given":"Alina","family":"Wo\u017aniak","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kar\u0142owicza 24, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World Stroke Organization: Global Stroke Fact Sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. 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