Pathophysiological mechanisms and therapeutic strategies of hepatic ischemia–reperfusion injury

Abstract Hepatic ischemia–reperfusion injury commonly occurs in conditions such as trauma, shock, hepatectomy, and liver transplantation. In the absence of timely intervention, severe cases may progress to liver failure, significantly affecting patient prognosis and surgical outcomes. Therefore, a comprehensive understanding of its pathological mechanisms, identification of potential adverse effects and limitations of current treatment strategies, and exploration of novel and effective therapeutic approaches are of great clinical significance. Researchers have established a variety of animal and cellular models demonstrating mitochondrial dysfunction, oxidative stress imbalance, multiple modes of programmed cell death (autophagy, apoptosis, pyroptosis, and ferroptosis), Kupffer cell activation, calcium overload, and upregulated pro-inflammatory cytokine signaling collectively drive hepatic injury; these processes are precisely modulated by the NF-κB, MAPK, and PI3K/AKT signaling axes, forming an intricate pathological network. Recent years have seen the clinical translation of various targeted intervention strategies, such as nanodrug delivery systems, machine perfusion, and multitarget pharmacological modulation. Through systematic searches of three major databases (PubMed, Web of Science, and Embase), this narrative review synthesizes current literature on hepatic ischemia–reperfusion injury (HIRI), with a focus on elucidating its signaling mechanisms, therapeutic targets, and challenges in clinical translation.