{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T11:02:55Z","timestamp":1777719775100,"version":"3.51.4"},"reference-count":96,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Hepatic ischemia\u2013reperfusion injury (IRI) remains a major challenge in liver transplantation (LTx) and hepatectomy. Previous studies identified a 12\/15-lipoxygenase (12\/15-LOX)-driven lipid peroxidation cascade promoting cell death, whereas glutathione peroxidase 4 (GPx4)-dependent metabolism acts antagonistically. This study investigated whether tacrolimus protects against hepatic IRI through this redox axis. Methods: Male C57BL\/6 mice underwent 65% partial hepatic warm ischemia and reperfusion with or without tacrolimus preconditioning. Liver tissue and serum were analyzed by spectral photometry, Western blotting, TUNEL assay, and serum enzyme measurement. Results were statistically analyzed and compared with previously published results of 12\/15-LOX inhibition by baicalein pretreatment and its carrier DMSO. Also, the combination of both tacrolimus and baicalein was investigated. Results: Tacrolimus increased the oxidative glutathione activity quotient (GSSG\/GSH) by 75.1% (p = 0.0302), attenuated MAPK signaling, reduced SAPK\/JNK by 84.6% (p = 0.0059), with ERK1\/2 showing a downward trend, decreased Caspase-3 activation by 66.9% (p &lt; 0.001) and PARP cleavage by 59.9% (p = 0.0330), and lowered TUNEL-positive cell death by 61.8% (p = 0.0015). Tacrolimus achieved hepatoprotection comparable to 12\/15-LOX inhibition, but without hepatotoxicity, whereas combined treatment conferred no additional benefit yet bore toxic properties. Conclusions: Tacrolimus preconditioning mitigates hepatic IRI through a glutathione-linked redox\u2013signaling\u2013cell death axis and exerts cytoprotective effects beyond immunosuppression.<\/jats:p>","DOI":"10.3390\/antiox15050557","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:46:11Z","timestamp":1777455971000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tacrolimus (FK506) Attenuates Hepatic Ischemia\u2013Reperfusion Injury via Oxidative Glutathione Metabolism and Suppression of Lipoxygenase-Mediated Cell Death"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0662-7643","authenticated-orcid":false,"given":"Moritz","family":"Drefs","sequence":"first","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5830-3536","authenticated-orcid":false,"given":"Malte J.","family":"Schirren","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-0032","authenticated-orcid":false,"given":"Dominik T.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1804-5090","authenticated-orcid":false,"given":"Severin J.","family":"Jacobi","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8453-5325","authenticated-orcid":false,"given":"Michael","family":"Neuberger","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesca M.","family":"Holdt","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-8051","authenticated-orcid":false,"given":"Bernhard W.","family":"Renz","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Faculty of Medicine, Ludwig Maximilian University, 80539 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-8401","authenticated-orcid":false,"given":"Markus O.","family":"Guba","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Transplantation Center Munich, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8001-8547","authenticated-orcid":false,"given":"Dionysios","family":"Koliogiannis","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"},{"name":"Transplantation Center Munich, LMU University Hospital, Ludwig Maximilian University, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S0014-4800(03)00008-X","article-title":"Hepatic ischemia\/reperfusion injury\u2014A fresh look","volume":"74","author":"Fondevila","year":"2003","journal-title":"Exp. 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