{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:15:10Z","timestamp":1790810110676,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The progression of heart failure (HF) following myocardial ischemia\/reperfusion (I\/R) injury is driven by regulated cell death. Unlike the restrained nature of apoptosis, pyroptosis and necroptosis are lytic processes that trigger inflammatory cascades, causing extensive collateral damage to the non-regenerative myocardium. Understanding the integrated regulation of these pathways (PANoptosis) is essential for limiting infarct expansion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We examined PANoptosis in rat I\/R and H9c2 OGD\/R models using transmission electron microscopy, immunofluorescence, and molecular markers (C-CASP3, N-GSDMD, p-MLKL). The functional hierarchy of the BIRC3-CASP8 axis was dissected using AAV-mediated gene transfer and pharmacological inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We confirmed that I\/R injury induces PANoptosis with interdependent crosstalk. Mechanistically, BIRC3 acted as a pivotal checkpoint: its upregulation inhibited CASP8, promoting membrane-rupturing pyroptosis and necroptosis. Crucially, BIRC3 silencing disinhibited CASP8, redirecting the cell death machinery toward apoptosis. This phenotypic shift preserved cell membrane integrity and minimized the release of inflammatory mediators, effectively halting the propagation of cell death to surrounding healthy cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>For cardiomyocytes destined to die, the BIRC3-CASP8 axis serves as a decisive switch between destructive and silent death modes. By leveraging this axis to shift PANoptosis toward an apoptosis-dominant phenotype, we can reduce the inflammatory storm and collateral injury. This offers a promising therapeutic paradigm to maximize the preservation of functional myocardium and arrest HF progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1875226","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:26:15Z","timestamp":1782707175000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["BIRC3-CASP8 axis orchestrates the PANoptosis spectrum: taming the inflammatory storm to prevent post-ischemic heart failure"],"prefix":"10.3389","volume":"17","author":[{"given":"Quancheng","family":"Han","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajing","family":"Yuan","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitao","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiding","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, 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