MIF Inhibitor ISO-1 Cuts Liver Reperfusion Injury in Rat Transplant Model

Blocking a single inflammatory molecule with a small-molecule inhibitor significantly reduced early liver damage in a rat model of donation after circulatory death (DCD) liver transplantation, according to a new experimental study. The drug, ISO-1, inhibits macrophage migration inhibitory factor (MIF), an early mediator of ischemia–reperfusion injury (IRI), the cascade of damage that occurs when blood flow returns to a graft after a period of oxygen deprivation.

DCD grafts are particularly vulnerable to IRI because they experience warm ischemia between cardiac arrest and procurement, on top of the cold storage period before implantation. While MIF’s role in ischemia–reperfusion injury is established in other contexts, its contribution in orthotopic liver transplantation, especially with DCD grafts, had remained poorly characterized.

The researchers used 196 male Lewis rats randomized into five groups: donation after brain death (DBD) controls, 30-minute DCD grafts, 60-minute DCD grafts, 30-minute DCD grafts treated with ISO-1, and 30-minute DCD grafts given vehicle. ISO-1 was administered before controlled cardiac arrest (0–60 minutes) and again during 3 hours of cold preservation before arterialized orthotopic liver transplantation. Animals were sacrificed at 1, 3, 24, and 168 hours after reperfusion, with seven animals per group per time point.

The DCD grafts showed marked injury, and the 60-minute DCD group exhibited lethal ischemia–reperfusion injury, underscoring how quickly warm ischemia pushes these grafts past a recoverable threshold. Against that backdrop, ISO-1 pre-treatment produced clearly measurable benefits in the 30-minute DCD group.

ISO-1 significantly reduced early hepatocellular injury compared with vehicle. Serum AST, a marker of liver cell damage, measured 294 ± 63 IU/L in treated animals versus 867 ± 211 IU/L in vehicle controls (p = 0.017), bringing levels close to those of the DBD control group. The treated animals also showed lower serum levels of HMGB-1 (11 ± 2.8 versus 26 ± 6.2 pg/mL, p = 0.045) and MIF itself (45 ± 5.3 versus 144 ± 27.5 ng/mL, p = 0.034), both of which act as damage-associated molecular patterns (DAMPs) that amplify inflammation after reperfusion.

Beyond the blood markers, ISO-1 improved graft microcirculation at 24 hours and attenuated histological injury. The treatment was also associated with an altered time course of CD163-positive macrophage infiltration into the graft, pointing to a shift in the inflammatory response that follows reperfusion.

The authors conclude that 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. As an animal study, the work demonstrates effects in a rat model rather than proven clinical benefit, and the findings will need validation in larger and translational settings before any application to human transplantation can be considered.

Subject of Research: MIF inhibition with ISO-1 in a rat model of DCD liver transplantation ischemia-reperfusion injury

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

Article References: Uluk, D., Liu, W., Jiang, D., Stoppe, C., Meister, F. A., Kraemer, S., Beckers, C., Theissen, A., Bleilevens, C., Bednarsch, J., Neumann, U. P., Tolba, R. H., & Czigany, Z. (2026). MIF inhibitor ISO-1 attenuates ischemia-reperfusion injury in a rat model of donation after circulatory death liver transplantation. PLOS One, 21(10), e0361214. https://doi.org/10.1371/journal.pone.0361214

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361214

Keywords: MIF, ISO-1, ischemia-reperfusion injury, DCD liver transplantation, rat model, DAMPs, HMGB-1, microcirculation, macrophages, graft injury, orthotopic liver transplantation, inhibitor