{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:23:17Z","timestamp":1788355397372,"version":"build-2803163510"},"reference-count":101,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["H2020-MSCA-ITN-ETN-2016"],"award-info":[{"award-number":["H2020-MSCA-ITN-ETN-2016"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Static cold storage (SCS) remains the most widely used method of liver graft preservation due to its simplicity, accessibility, and reduced cost in transplantation practice. Since the invention of the University of Wisconsin (UW) solution, several alternative preservation solutions\u2014including histidine\u2013tryptophan\u2013ketoglutarate (HTK), Celsior, and more recently IGL-1 and IGL-2\u2014have been formulated to optimize cellular and vascular protection during cold ischemia. More recently, the introduction of dynamic perfusion techniques, such as hypothermic oxygenated perfusion (HOPE) and normothermic machine perfusion (NMP), approximately fifteen years ago, has further enhanced transplantation protocols, being applied either alone or in combination with traditional SCS to ensure optimal graft preservation prior to implantation. Despite these technological advances, achieving fully effective dynamic perfusion remains a key challenge for improving outcomes in vulnerable grafts, particularly steatotic or marginal livers. This review details how Polyethylene Glycol 35 (PEG35)-based solutions activate multiple cytoprotective pathways during SCS, including AMP-activated protein kinase (AMPK), nitric oxide (NO) production, and the antioxidant transcription factor Nrf2. We propose that these molecular mechanisms serve as a form of preconditioning that is synergistically leveraged by HOPE to preserve mitochondrial function, endothelial glycocalyx integrity, and microvascular homeostasis. Furthermore, the oncotic and rheological properties of PEG35 reduce perfusate viscosity, mitigating shear stress and microcirculatory damage during dynamic perfusion\u2014effects that are further enhanced by NO- and AMPK-mediated protection initiated during the SCS phase. This integrated approach provides a strong rationale for combining PEG35-mediated SCS with HOPE, particularly for grafts with high susceptibility to ischemia\u2013reperfusion injury, such as fatty livers. Finally, we highlight emerging avenues in graft preservation, including the design of unified perfusion solutions that optimize endothelial, mitochondrial, and redox protection, with the potential to improve post-transplant outcomes and extend applicability to other solid organ grafts.<\/jats:p>","DOI":"10.3390\/ijms262311734","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T13:53:30Z","timestamp":1764856410000},"page":"11734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Static Cold Storage and Machine Perfusion: Redefining the Role of Preservation and Perfusate Solutions"],"prefix":"10.3390","volume":"26","author":[{"given":"Arnau","family":"Panisello-Rosello","sequence":"first","affiliation":[{"name":"Translational Research and Innovation in General and Digestive Surgery (GITIC), Department of General and Digestive Surgery, La Paz University Hospital\u2013IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7131-3667","authenticated-orcid":false,"given":"Teresa","family":"Carbonell","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Rosello-Catafau","sequence":"additional","affiliation":[{"name":"Steatohepatitis and Liver Transplantation Unit, Institut d\u2019Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), 08037 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5628-9876","authenticated-orcid":false,"given":"Jordi","family":"Vengohechea","sequence":"additional","affiliation":[{"name":"Translational Research and Innovation in General and Digestive Surgery (GITIC), Department of General and Digestive Surgery, La Paz University Hospital\u2013IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Hessheimer","sequence":"additional","affiliation":[{"name":"Translational Research and Innovation in General and Digestive Surgery (GITIC), Department of General and Digestive Surgery, La Paz University Hospital\u2013IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Adam","sequence":"additional","affiliation":[{"name":"Centre H\u00e9pato-Biliaire, AP-HP, H\u00f4pital Paul Brousse, Villejuif, 94800 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6161-6824","authenticated-orcid":false,"given":"Constantino","family":"Fondevila","sequence":"additional","affiliation":[{"name":"Translational Research and Innovation in General and Digestive Surgery (GITIC), Department of General and Digestive Surgery, La Paz University Hospital\u2013IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nrgastro.2012.225","article-title":"Ischaemia\u2013reperfusion injury in liver transplantation\u2014From bench to bedside","volume":"10","author":"Zhai","year":"2013","journal-title":"Nat. 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