Organ- and Cell-Specific Induction of the NFE2L2 Antioxidant Programme After Human Graft Reperfusion

Reactive oxygen species at reperfusion are held as a shared injury mechanism across organs, so antioxidant strategies are systemic. Whether the graft's own response is uniform is untested in human tissue.

Eight public cohorts of paired pre/post-reperfusion human transplant biopsies (kidney, 96 pairs; liver, 40; lung, 54) were analysed with a pre-specified 99-gene antioxidant/ROS panel in ten modules. Within-person differences were compared between organs (paired Wilcoxon, Benjamini-Hochberg) and pooled by random-effects meta-analysis. Two single-cell datasets (lung, 117,549 cells, six recipients; liver, 8802 cells, one donor) resolved cell type. All measures are transcriptional.

Antioxidant transcription did not rise as a whole: constitutive scavenging enzyme transcripts fell or were unchanged in every organ. Increase was confined to the NFE2L2-dependent antioxidant programme, graded by organ (lung 98.1%, liver 92.5%, kidney 62.5%; pooled d_z 0.99, I² = 89%), with 72.5% of that heterogeneity attributable to organ and no covariate significant after correction. Single-cell data support involvement of epithelium, endothelium, fibroblasts and resident macrophages, but not recruited myeloid cells.

At the transcript level the reperfusion response is an inducible programme of graded completeness in resident graft cells. Whether antioxidant intervention must be directed by organs, timing and cell type remains untested.