Macrophage polarization in ischemia-reperfusion injury: from molecular mechanisms to therapeutic strategies

Ischemia-reperfusion injury (IRI) induces secondary tissue damage following the restoration of blood flow. Currently, there is a lack of specific therapeutic interventions for IRI. Macrophage M1/M2 polarization plays a pivotal role in the progression of IRI; however, integrated analyses of its dynamic changes and organ-specific characteristics remain insufficient. This review focuses on the critical role of macrophage M1/M2 phenotypic balance in IRI, systematically elucidating the mechanisms underlying its dynamic regulation. It highlights, for the first time, the impact of metabolic reprogramming and mechanical signaling on polarization imbalance and provides a comprehensive analysis of the organ-specific features of macrophages in four common target organs of reperfusion injury (heart, brain, liver, and kidney). In terms of interventional strategies, cutting-edge approaches are emphasized, including epigenetic drugs, nanoparticle-based targeted delivery systems, and temporally sequenced combination therapies, to achieve precise temporal regulation from suppression of M1-mediated inflammation to promotion of M2-driven repair. In the future, integration of multi-omics and spatiotemporal dynamic analyses will be essential to construct organ-specific and stage-adaptive immune intervention frameworks, thereby advancing the treatment of IRI toward personalization and precision medicine.