Pathological mechanisms of hepatic ischemia-reperfusion injury and stem cell–based therapeutic strategies: Mechanistic insights and translational perspectives

Hepatic ischemia-reperfusion injury (HIRI) remains a major clinical challenge in liver surgery, transplantation, and trauma, contributing to graft dysfunction and increased morbidity. This review summarizes the complex pathophysiology of HIRI, including metabolic derangements during ischemia, bursts of oxidative stress on reperfusion, and sterile inflammation driven by reactive oxygen species (ROS) and immune-cell activation. It also examines regulated cell death pathways-apoptosis, pyroptosis, necroptosis, and ferroptosis-that interact to create self-reinforcing cycles and further amplify tissue injury.Building on these mechanistic insights, the review highlights emerging therapeutic strategies centered on mesenchymal stem cells (MSCs) and MSC-derived products, including extracellular vesicles (EVs), exosomes, and conditioned medium. MSCs confer protection through immunomodulatory effects, such as promoting macrophage polarization toward anti-inflammatory phenotypes, as well as through cytoprotective mechanisms including antioxidant secretion and mitochondrial transfer. In addition, MSCs support tissue repair by enhancing regenerative responses. Preclinical studies consistently show that MSC-based interventions reduce oxidative stress, inflammation, and cell death. Early clinical trials in liver transplantation further suggest that MSC therapy is safe and may reduce ischemia-associated complications.Finally, this review discusses key translational barriers, including inefficient homing, donor-to-donor variability, and the need for standardized manufacturing and potency assessment. Future directions include MSC preconditioning, EV engineering, and combination approaches with machine perfusion technologies. By integrating mechanistic understanding with therapeutic advances, this review underscores the potential of MSC-based therapies to reshape HIRI management and highlights broader opportunities for regenerative medicine in organ injury.