PANoptosis in hepatic ischemia-reperfusion injury: An integrated cell death network linking inflammation and...

Hepatic ischemia-reperfusion injury is a common clinical challenge in liver surgery, involving complex mechanisms of cell death in its pathological process. Conventional single-target intervention strategies have shown limited efficacy, highlighting the need to explore novel regulatory approaches from a systemic perspective. In recent years, a novel integrated programmed cell death modality-PANoptosis-has emerged as a promising concept, offering new insights into untangling the intricate mechanisms of hepatic ischemia-reperfusion injury by synergistically activating molecular pathways of apoptosis, pyroptosis, and necroptosis. This review systematically summarizes the molecular components and signaling regulatory networks of PANoptosis, as well as its activation mechanisms in hepatic ischemia-reperfusion injury. It particularly elaborates on its pathological effects in both hepatocytes and non-parenchymal cells, such as hepatic sinusoidal endothelial cells and Kupffer cells, and analyzes the crosstalk and synergistic interactions between PANoptosis and other forms of cell death. Studies have revealed that metabolic stress, oxidative stress, and the release of damage-associated molecular patterns can induce mitochondrial dysfunction, leading to the coordinated activation of multiple pathways that exacerbate liver injury and amplify inflammation. Both animal models and cellular experiments have confirmed that specific knock out of key molecules or the use of small-molecule inhibitors can significantly mitigate liver damage. Furthermore, natural products, gene-editing technologies, and preconditioning strategies have also demonstrated considerable interventional potential. However, current research still faces limitations, including insufficient mechanistic depth, a disconnect between animal models and clinical relevance, and inadequate understanding of the interactive regulation among multiple cell death modalities. Future studies should focus on elucidating cell type-specific mechanisms, developing humanized models, integrating multi-omics analyses, and promoting the clinical translation of targeted therapeutics. These efforts are expected to facilitate a shift from single-target interventions toward multidimensional and systemic treatment strategies, thereby providing theoretical support and practical pathways for improving outcomes in patients undergoing liver surgery.