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Published on: February 27, 2026
Human Biopsy-Defined IRI-Selective Reperfusion Signature Prioritizes Reperfusion-Timed MEK Inhibition After DCD Liver
Yongqiang Zhao1, Dong Hou2, Bowen Xiong3
1Department of General Surgery, Third Division, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
Summary
Targeting early liver transplant injury in donation after circulatory death (DCD) grafts is crucial. This study identifies MEK inhibition at reperfusion as a promising strategy to reduce ischemia-reperfusion injury (IRI) and improve graft survival.
Area of Science:
- Transplantation immunology
- Molecular biology
- Bioinformatics
Background:
- Early ischemia-reperfusion injury (IRI) in liver grafts from donation after circulatory death (DCD) lacks targeted therapies.
- Generic reperfusion transcriptional changes obscure IRI-specific responses, hindering therapeutic development.
- There is a critical need for therapies targeting the immediate post-reperfusion window in DCD liver transplantation.
Purpose of the Study:
- To define an IRI-selective early reperfusion program using paired liver biopsies.
- To identify molecular targets and potential therapeutic strategies for early IRI in DCD liver grafts.
- To evaluate the efficacy of MEK inhibition in mitigating IRI in a preclinical liver transplant model.
Main Methods:
- Analysis of paired pre-/post-reperfusion liver biopsies from two human cohorts (GSE151648, GSE87487) using a difference-in-differences (ΔΔ) interaction estimand.
- Genome-wide ΔΔ effects summarized by PROGENy and pathway analysis; identification of perturbagens using L1000CDS2.
- In vitro assessment of MEK inhibitor (PD-0325901) on hepatocyte injury and in vivo evaluation in a rat DCD liver transplantation model.
Main Results:
- A reproducible ΔΔ footprint highlighted EGFR-MAPK signaling as a key pathway in early IRI.
- Cross-cohort analysis identified MEK1/2 inhibitors as shared perturbagens, with MEK/ERK engagement localized to parenchymal cells.
- MEK inhibition with PD-0325901 reduced hepatocyte injury, attenuated IRI in a rat DCD liver transplant model, and improved survival.
Conclusions:
- The biopsy-anchored ΔΔ interaction-phenotype framework successfully identified IRI-selective molecular programs.
- Reperfusion-timed MEK inhibition is a mechanism- and window-aligned strategy to blunt early post-liver transplant IRI.
- This approach nominates MEK inhibitors as a potential therapeutic intervention for DCD liver grafts.
