Modeling Hepatic Ischemia-Reperfusion Injury: From 2D and Animal Models to Advanced 3D Platforms

Hepatic ischemia-reperfusion injury (IRI) is one of the main clinical challenges in liver surgery and transplantation, contributing to postoperative complications and graft dys-function. The pathogenesis of hepatic IRI is complex and multifactorial, involving meta-bolic consequences induced by ischemia, oxidative stress, inflammatory responses, endo-thelial dysfunction, and the activation of immune pathways upon reperfusion. Despite extensive research efforts, the translation of preclinical findings into effective clinical in-terventions has been limited. This review provides a critical overview of the most im-portant models employed to investigate hepatic IRI. Conventional two-dimensional (2D) in vitro systems, including monocultures and co-culture models, offer controlled envi-ronments for mechanistic studies and high-throughput screening but fail to fully repro-duce the structural and cellular complexity of the liver microenvironment. Animal mod-els, particularly those based on mice, rats, and pigs, remain essential for studying the sys-temic and multicellular aspects of hepatic IRI. However, species-specific physiological differences, ethical concerns, high costs, and limited translational predictability represent significant limitations. In this context, three-dimensional (3D) liver models have emerged as promising alternatives able to bridge the gap between in vitro systems and animal ex-perimentation. By better recapitulating tissue architecture, cell-cell interactions, and func-tional heterogeneity, 3D platforms offer improved physiological relevance and transla-tional potential. In detail, we discuss the strengths and limitations of each experimental approach and highlight the role of advanced 3D models as complementary tools that may facilitate more accurate investigations of hepatic IRI and accelerate the development of therapeutic strategies.