Damage-associated molecular patterns in hepatic ischemia-reperfusion injury: spatiotemporal signatures, biomarker potential, and clinical translation

Hepatic ischemia-reperfusion injury (HIRI) remains a key contributor to early allograft dysfunction (EAD), post-hepatectomy liver failure, biliary complications, and the underutilization of marginal donor grafts. Damage-associated molecular patterns (DAMPs) are central mediators of sterile inflammation in HIRI; however, their translational relevance extends beyond being upstream inflammatory triggers. In this review, we reframe DAMP biology by considering spatiotemporal release, sampling accessibility, biomarker utility, and therapeutic tractability. Rather than providing another broad overview of sterile inflammation or regulated cell death, we focus on how distinct DAMP classes-including nuclear and nucleic acid-related signals, mitochondrial and metabolic DAMPs, extracellular matrix-derived fragments, and protein-based danger cues-arise from defined cellular sources during cold ischemia, warm ischemia, early reperfusion, and late injury-repair phases. We discuss how these signals are detected by pattern-recognition receptors (PRRs) and intracellular sensing pathways, including Toll-like receptors (TLRs), receptor for advanced glycation end products (RAGE), the P2X purinoceptor 7 (P2X7)-NLR family pyrin domain-containing 3 (NLRP3) inflammasome axis, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. We further examine how DAMP-driven sensing coordinates Kupffer cell activation, endothelial dysfunction, neutrophil-mediated amplification, thromboinflammation, and impaired tissue recovery. Particular emphasis is placed on circulating and perfusate-accessible DAMP signatures as minimally invasive tools for injury grading, EAD prediction, biliary complication risk stratification, and donor graft-quality assessment during machine perfusion. We also summarize DAMP-targeted therapeutic strategies, including strategies to limit DAMP release, enhance extracellular DAMP clearance, block dominant sensing pathways, and integrate DAMP modulation with organ-preservation platforms. Finally, we highlight key barriers to clinical translation, including assay heterogeneity, undefined sampling windows, insufficient multicenter validation, and the need to distinguish reparative from pathogenic DAMP signaling. A spatiotemporal, DAMP-centered framework may help connect molecular injury biology with biomarker-guided decision-making and precision interventions in liver transplantation and hepatic surgery.