Stress pathways driving ischemia–reperfusion injury in the aged liver and consequences for post-transplant outcomes

Background Cold ischemia time (CIT) represents a pivotal, potentially modifiable determinant of ischemia–reperfusion injury (IRI) and early allograft dysfunction. Its influence is particularly pronounced in extended-criteria and older donor livers, yet the mechanistic links have not been examined in an age- and CIT-focused integrative manner. Objective To integrate clinical and experimental evidence to clarify how prolonged CIT amplifies IRI in the aged liver, to delineate convergent and interacting molecular pathways, and to summarize therapeutically actionable strategies with translational potential. Review Scope and Search Strategy To ensure transparency in this narrative review, a structured literature search was conducted across PubMed/MEDLINE and Web of Science from database inception to March 2026 for English-language publications. The search strategy utilized Boolean combinations of MeSH terms and keywords: [ 1 ] "liver transplantation", "hepatic transplantation", or "liver graft"; [ 2 ] "aging", "aged donor", "elderly donor", or "extended criteria donor" intersected with "cold ischemia time", "CIT", "ischemia-reperfusion injury", or "IRI"; and [ 3 ] "ferroptosis", "mitochondrial dysfunction", "endoplasmic reticulum stress", "ERS", "UPR", "machine perfusion", "HOPE", or "NMP". Inclusion and Exclusion Criteria Peer-reviewed original research was eligible if it investigated: (i) hepatic IRI in the context of donor aging or prolonged CIT; (ii) convergent ferroptosis, mitochondrial collapse, or ERS-UPR axes; or (iii) post-transplant outcomes (EAD, biliary complications, graft survival). Non-English papers, case reports (n < 5), conference abstracts, and pediatric-only studies or models were excluded. Data Integration Retrieved evidence was categorized into two complementary streams within this narrative framework: preclinical studies ( in vitro and in vivo models) mapped molecular cross-talk and organelle interactions, while clinical registries and cohorts defined operational risk thresholds, collectively aligning molecular vulnerability with clinical risk stratification. The literature identification and screening process is summarized in a PRISMA-style flow diagram (Supplementary Figure S1). Results Longer CIT is linked to higher early allograft dysfunction and worse short-term outcomes, with larger effects in older and other extended-criteria grafts. Prolonged CIT promotes lipid peroxidation and iron dysregulation with impaired antioxidant defenses (Nrf2–SLC7A11–GSH–GPX4), disrupts mitochondrial energetics and quality control with excess ROS and mitophagy imbalance, and sustains maladaptive ERS–UPR signaling. These pathways amplify each other, driving cell death, microcirculatory failure, and sterile inflammation. HOPE/NMP and solution optimization may reduce injury, whereas drugs and exosome adjuncts need translational validation. Conclusion Advanced donor age and prolonged CIT may interact as a mechanistic working hypothesis, aggravating IRI through an interconnected network involving ferroptosis, mitochondrial dysfunction, and maladaptive ERS–UPR signaling. The proposed age × CIT framework should be interpreted as a center-adapted risk-alert heuristic rather than a validated prediction, allocation, or graft-discard rule.