{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:11:36Z","timestamp":1790248296373,"version":"4.1.0"},"reference-count":0,"publisher":"The Nencki Institute of Experimental Biology, Polish Academy of Sciences","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Acta Neurobiol. Exp."],"abstract":"<jats:p>Ischemia\u2013reperfusion injury remains a major cause of mortality and disability worldwide, with limited therapeutic options. While reperfusion is essential for tissue salvage, it paradoxically triggers secondary damage, highlighting the need to better understand regulated cell death pathways. Traditionally, apoptosis was considered the dominant mechanism; however, incomplete protection by caspase inhibition revealed a substantial contribution of caspase\u2011independent death. Among these, necroptosis has emerged as a functionally purposeful process, eliminating compromised cells but simultaneously amplifying sterile inflammation through the release of damage\u2011associated molecular patterns. This review synthesizes current knowledge of necroptosis in ischemia\u2013reperfusion injury. We first establish its functional relevance, then examine canonical and non\u2011canonical molecular pathways, including RIPK1\u2013RIPK3\u2013MLKL signaling, mitochondrial dysfunction, and CaMKII\u03b4\u2011mediated execution. We discuss mechanisms of CASP8 checkpoint weakening and bypass, emphasizing the roles of metabolic collapse, oxidative stress, and ZBP1\u2011mediated signaling. Finally, we highlight the cell\u2011type and temporal dynamics of necroptosis, as well as its translational implications. Recognizing necroptosis as a context\u2011dependent permissive state rather than a simple backup pathway provides a more comprehensive framework for understanding ischemic cell death and its tissue\u2011specific manifestations.<\/jats:p>","DOI":"10.55782\/qj1kb197","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:42:15Z","timestamp":1790246535000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional relevance and mechanisms of necroptosis in ischemia\u2013reperfusion injury"],"prefix":"10.55782","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0708-6594","authenticated-orcid":true,"given":"Roman","family":"Koval","sequence":"first","affiliation":[{"name":"Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6428-8646","authenticated-orcid":true,"given":"Iryna","family":"Lushnikova","sequence":"additional","affiliation":[{"name":"Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-651X","authenticated-orcid":true,"given":"Oleg","family":"Tsupykov","sequence":"additional","affiliation":[{"name":"Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-6178","authenticated-orcid":true,"given":"Galyna","family":"Skibo","sequence":"additional","affiliation":[{"name":"Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"34635","published-online":{"date-parts":[[2026,9,24]]},"container-title":["Acta Neurobiologiae Experimentalis"],"original-title":[],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:42:15Z","timestamp":1790246535000},"score":1,"resource":{"primary":{"URL":"https:\/\/ane.pl\/index.php\/ane\/article\/view\/2809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.55782\/qj1kb197","relation":{},"ISSN":["1689-0035","0065-1400"],"issn-type":[{"value":"1689-0035","type":"electronic"},{"value":"0065-1400","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}