Advancing our understanding of molecular targets for hepatic ischemia-reperfusion injury therapy

INTRODUCTION: Hepatic ischemia-reperfusion injury (IRI) remains a challenge in liver transplantation (LT), particularly with the increasing utilization of marginal grafts. Driven by ischemic stress and hemodynamic instability, IRI triggers intricate inflammatory responses. There is an urgent need to address this challenge by translating mechanistic insights into clinical practice. AREAS COVERED: This review examines IRI mechanisms across diverse cell types and assesses new therapeutic targets identified in recent preclinical and clinical research. It also addresses the implications of IRI in the context of pre-transplant machine perfusion (MP), highlighting approaches to reduce injury and improve graft function, especially in marginal or high-risk liver grafts. EXPERT OPINION: Hepatic IRI research is evolving despite historical challenges like species variability and reliance on rodent models. Advances in MP and studies on discarded human livers now provide clinically relevant validation platforms. This progress shifts our focus toward a vital goal: salvaging marginal grafts to alleviate the global donor organ shortage. Because the intricate nature of IRI limits single-pathway therapies, comprehensive strategies targeting mitochondria, reactive oxygen species, and hepatoprotection are gaining traction. Additionally, basic research should harness big data to identify therapeutic targets that are both highly translatable and reliable, ensuring more effective clinical solutions.