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Emerging data supports ferroptosis (iron regulated hepatocellular death) as an IRI driver, however lack of robust preclinical model limits therapeutic testing. In this manuscript we describe the development of a novel rigorous internal control system utilizing normothermic perfusion of split livers to test ferroptosis regulators modulating IRI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Upon institutional approval, split human MDLs were placed on our normothermic perfusion machine, Perfusion Regulated Organ Therapeutics with Enhanced Controlled Testing (PROTECT), pumping arterial and portal blood. Experiment 1 compared right (UR) and left (UL) lobes to validate PROTECT. Experiment 2 assessed ferroptosis regulator Deferoxamine in Deferoxamine Agent Treated (DMAT) vs. No Agent Internal Control (NAIC) lobes. Liver serology, histology, and ferroptosis genes were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Successful MDL perfusion validated PROTECT with no ALT or AST difference between UR and UL (\u2206ALT UR: 235, \u2206ALT UL: 212; \u2206AST UR: 576, \u2206AST UL: 389). Liver injury markers increased in NAIC vs. DMAT (\u2206ALT NAIC: 586, \u2206ALT DMAT: \u2010405; \u2206AST NAIC: 617, \u2206AST DMAT: \u2010380). UR and UL had similar expression of ferroptosis regulators RPL8,HO\u20101 and HIF\u03b1. Significantly decreased intrahepatic iron (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.038), HO\u20101 and HIF\u03b1 in DMAT (HO\u20101 NAIC: 6.93, HO\u20101 DMAT: 2.74; HIF\u03b1NAIC: 8.67, HIF\u03b1DMAT: 2.60)and no hepatocellular necrosis or immunohistochemical staining (Ki67\/Cytokeratin\u20107) differences were noted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PROTECT demonstrates the therapeutic utility of a novel normothermic perfusion split liver system for drug discovery and rapid translatability of therapeutics, driving a paradigm change in organ recovery and transplant medicine. Our study using human livers, provides preliminary proof of concept for the novel role of ferroptosis regulators in driving IRI.<\/jats:p><\/jats:sec>","DOI":"10.1111\/petr.14164","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T10:08:40Z","timestamp":1634206120000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel NMP split liver model recapitulates human IRI and demonstrates ferroptosis modulators as a new therapeutic strategy"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8437-6085","authenticated-orcid":false,"given":"Mustafa","family":"Nazzal","sequence":"first","affiliation":[{"name":"Department of Surgery Saint Louis University School of Medicine Saint Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik C.","family":"Madsen","sequence":"additional","affiliation":[{"name":"Department of 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