MIF inhibitor ISO-1 attenuates ischemia-reperfusion injury in a rat model of donation after circulatory death liver transplantation

Macrophage migration inhibitory factor (MIF) is an early mediator of ischemia-reperfusion injury (IRI), however, the evidence on its role in orthotopic liver transplantation (OLT), particularly with donation after circulatory death (DCD) grafts is limited. Given its key regulatory function, this study investigated the effects of IRI on graft injury and assessed whether the use of ISO-1, a small-molecule MIF-inhibitor, affect IRI in a rat DCD-OLT model. 196 male Lewis rats were randomized into DBD control, DCD-30 min, DCD-60 min, DCD-30 + ISO-1, and DCD-30 + vehicle groups (n = 7/group/time-point). ISO-1 was administered before controlled cardiac arrest (0-60 min) and 3 h cold preservation before arterialized OLT. Animals were sacrificed at 1, 3, 24, and 168 h post-reperfusion. DCD grafts showed marked injury, with the DCD-60 group exhibiting lethal IRI. ISO-1 significantly reduced early hepatocellular injury compared with vehicle (AST:294 ± 63 vs 867 ± 211 IU/L, p = 0.017) and resulted in values comparable to DBD controls. Serum HMGB-1 (11 ± 2.8 vs 26 ± 6.2 pg/mL, p = 0.045) and MIF (45 ± 5.3 vs 144 ± 27.5 ng/mL, p = 0.034) levels were similarly decreased following ISO-1 application. ISO-1 improved graft microcirculation at 24 h, attenuated histological injury, and was associated with an altered time course of CD163 + macrophage infiltration. ISO-1 pre-treatment attenuated hepatocellular injury and was associated with improved graft microcirculation and reduced DAMP release, supporting further mechanistic and translational evaluation in DCD liver transplantation.