At the transcript level, the reperfusion response in human grafts is an inducible NFE2L2-dependent antioxidant programme of graded completeness (lung > liver > kidney) in resident graft cells, rather than a uniform rise in antioxidant transcription.
Antioxidant transcription did not rise as a whole after human graft reperfusion; constitutive scavenging enzyme transcripts fell or were unchanged in every organ.
Increased transcription was confined to the NFE2L2-dependent antioxidant programme.
The NFE2L2-dependent programme was induced in a graded manner by organ: lung > liver > kidney.
Organ explained most of the heterogeneity in the NFE2L2 programme response, and no covariate was significant after correction.
Single-cell data support involvement of resident graft cells but not recruited myeloid cells in the NFE2L2 antioxidant response.
The reperfusion antioxidant response is an inducible programme of graded completeness in resident graft cells, challenging the assumption of a uniform response across organs.
This study looked at gene activity in human transplanted organs (kidney, liver, lung) sampled before and after blood flow was restored. Restoring blood flow produces damaging reactive oxygen molecules, and it is often assumed that all organs respond the same way, so antioxidant treatments are thought to apply broadly. The researchers combined eight public datasets to test whether the grafts' own antioxidant response is actually uniform. They found that antioxidant gene activity did not simply go up across the board. Genes for the cell's standing antioxidant enzymes stayed the same or fell in every organ. What rose was a specific set of genes controlled by the NFE2L2 stress-response pathway, and the size of the rise differed by organ: nearly all lungs (98.1%) and livers (92.5%) showed an increase, compared with about 62.5% of kidneys. Organ type accounted for most of the variation between studies. Single-cell data suggested the response came from the organ's own resident cells (lining cells, blood vessel cells, fibroblasts, resident macrophages) and not from immune cells arriving from the blood. This research suggests the graft's response to reperfusion differs between organs, which may matter for designing antioxidant treatments. However, the work measured only gene transcripts, not protein or actual oxidative damage, and the liver single-cell data came from a single donor. Whether treatments need to be tailored by organ, timing, or cell type has not been tested.
Oh H, Ahn S. (2026). Organ- and Cell-Specific Induction of the NFE2L2 Antioxidant Programme After Human Graft Reperfusion.. Biomolecules. https://doi.org/10.3390/biom16101485