Liver ischemia reperfusion injury: Mechanisms, cellular pathways, and therapeutic approaches

Liver ischemia-reperfusion injury (LIRI) is a critical challenge in liver transplantation, resection, and trauma surgeries, leading to significant hepatic damage due to oxidative stress, inflammation, and mitochondrial dysfunction. This review explores the cellular and molecular mechanisms underlying LIRI, focusing on ATP depletion, mitochondrial dysfunction, and the involvement of reactive oxygen species (ROS). Inflammatory pathways, including the activation of nuclear factor-kappa B (NF-κB) and the NLRP3 inflammasome, as well as pro-inflammatory cytokines such as TNF-α and IL-1β, play a crucial role in exacerbating tissue damage. Various types of cell death, including necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis and cuproptosis are also discussed. Therapeutic interventions targeting these mechanisms, such as antioxidants, anti-inflammatories, mitochondrial protectors, and signaling modulators, have shown promise in pre-clinical studies. However, translating these findings into clinical practice faces challenges due to the limitations of animal models and the complexity of human responses. Emerging therapies, such as RNA-based treatments, genetic editing, and stem cell therapies, offer potential breakthroughs in LIRI management. This review highlights the need for further research and the development of innovative therapeutic approaches to improve clinical outcomes.