Dynamic regulation and targeted intervention of neutrophils in hepatic ischemia‑reperfusion injury (Review)

Ischemia‑reperfusion injury (IRI) is a complex pathophysiological process characterized by oxidative stress, inflammatory response and cell death during tissue reperfusion, leading to organ dysfunction. In liver transplantation, hepatic ischemia‑reperfusion injury (HIRI) can result in irreversible liver failure and subsequently trigger rejection. Neutrophils, as the first recruited innate immune cells, play a central role in the initiation, progression and resolution stages of HIRI. However, current research predominantly focuses on their pro‑inflammatory and damaging mechanisms, lacking a theoretical framework that systematically integrates their dual functions. Based on a systematic review of key processes involving neutrophils in HIRI, including recruitment, adhesion, migration, neutrophil extracellular trap (NET) formation and phenotypic polarization, the present review proposed the 'injury‑repair balance' theory. It emphasized that neutrophils are dynamically regulated by the hepatic microenvironment and can undergo functional conversion between pro‑inflammatory N1 and anti‑inflammatory/repair N2 phenotypes. Their polarization state is a critical factor determining the progression and recovery of HIRI. The present review further explores multi‑dimensional intervention strategies targeting neutrophils, including inhibiting excessive recruitment and activation, regulating migration to reduce local accumulation, suppressing NET formation and promoting their clearance, as well as combining antioxidant and anti‑inflammatory therapies to reestablish immune homeostasis. Additionally, extracellular vesicles, due to their excellent targeting delivery and immunomodulatory capabilities, have emerged as potential tools for precise regulation of neutrophil function. Notably, current research on neutrophil polarization mechanisms remains incomplete. Future studies should delve into the temporal regulatory mechanisms of polarization and explore the possibility of driving neutrophils toward an N2‑like reparative phenotype through pharmacological or biological interventions. This strategy is expected to shift the treatment paradigm for HIRI from traditional 'cell suppression' to a more precise 'functional reprogramming,' transforming the approach from merely mitigating injury to actively promoting tissue regeneration.