Ischemia–Reperfusion Injury: Molecular Mechanisms and Therapeutic Interventions

ABSTRACT Ischemia–reperfusion injury (IRI) is a common pathological process underlying cardiovascular events, organ transplantation, and shock resuscitation. Its paradox is that restoration of blood flow, while essential for tissue survival, can itself intensify cellular stress and amplify tissue damage. This review delineates the cross‐organ mechanistic cascade of IRI, beginning with metabolic collapse, adenosine triphosphate (ATP) depletion, and ionic dysregulation during ischemia, and progressing to reperfusion‐driven mitochondrial dysfunction, oxidative and nitrosative stress, and activation of regulated cell death programs. We further highlight how sterile inflammation evolves into a coordinated endothelial–immune–coagulation interaction network centered on neutrophil extracellular traps (NETs), which couple microvascular obstruction with inflammatory signaling to promote immunothrombosis and propagate injury locally and to distant organs. Despite major advances in mechanistic insight, translation into effective therapies remains inconsistent, largely due to phenotypic heterogeneity, narrow therapeutic windows, and the lack of real‐time biomarkers that capture pathway activity. Future progress will require a systems‐level, cross‐organ framework for immune remodeling, with particular emphasis on targetable NET‐driven immunothrombotic phenotypes. Biomarker‐guided precision stratification, multimodal data integration, ex vivo machine perfusion platforms, and organoid‐based human models may enable mechanism‐aligned trials and shift therapy from macroscopic reperfusion toward microvascular stabilization and cellular repair.