RUNX1 in liver graft ischemia-reperfusion injury: a cell-specific framework for ex vivo intervention.

Hepatic ischemia-reperfusion injury (HIRI) remains a major obstacle to the use of marginal donor livers. RUNX1 has not yet been established as a causal regulator of acute HIRI, and several transcription factors have stronger disease-specific evidence. We therefore asked whether existing human transplant datasets could help define where a RUNX1 hypothesis is most plausible. In 80 paired pre- and post-reperfusion biopsies from 40 recipients (GSE151648), RUNX1 increased after reperfusion (log2 fold change 1.449; FDR 1.65e-28), although the between-group difference in within-patient change was not significant for the biopsy-defined IRI-positive and IRI-negative groups. In the single-transplant GSE171539 dataset, RUNX1-high myeloid cells increased from 10.5% before procurement and 10.1% at the end of preservation to 32.9% at 2 h after reperfusion, with the signal concentrated in inflammatory monocyte and Kupffer/macrophage-like states. These observations support prioritizing the myeloid compartment for direct testing but do not establish causality. We outline distinct working hypotheses for myeloid cells, liver sinusoidal endothelial cells (LSECs), and hepatocytes, and argue that transient pharmacological or targeted RNA perturbation is better suited to the acute reperfusion window than durable viral expression. Translation will require a staged path from causal models to discarded-human-liver perfusion and, ultimately, transplantation after ex vivo treatment.