Geraldine Veeckmans, Lene Devos, Nicholas Gilbo, Dieter Van Beersel, Camilla Scarpellini, Joris Blondeel, Magali Walravens, Greta Klejborowska, Caroline Lanthier, Michele Wölk, Sebastian Müller, Christine Gaillet, Ludovic Colombeau, Behrouz Hassannia, Matthias Längin, Martin Bender, Jan‐Michael Abicht, B Reichart, H. Winter, Maria Fedorova, Raphaël Rodriguez, J. Pirenne, Laurens J. Ceulemans, Ina Jochmans, Koen Augustyns, Diethard Monbaliu, Arne Neyrinck, Tom Vanden Berghe
Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iron-dependent form of cell death, leading to organ dysfunction. We identify an early and transient increase of lipid peroxidation in human liver transplants and validate it as a therapeutic target. FXT-001, a ferroptosis inhibitor with dual radical and iron-trapping activity, provides robust protection in preclinical models, including ex situ perfusion of porcine liver and lung grafts. In a split ex vivo machine perfusion setting using declined human donors, FXT-001 treatment preserves graft viability, whereas untreated lungs deteriorate. We also develop FXT-002 and FXT-003 with enhanced pharmacokinetic and safety profiles. These findings support the use of ferroptosis inhibitors as a therapeutic strategy in transplantation and other IRI-associated conditions.