Precision Oxygen Modulation in the Reperfusion Era: Conditioning and Therapeutic Strategies in Ischemic Stroke

Endovascular thrombectomy (EVT) and advanced perfusion imaging have transformed acute ischemic stroke (AIS) treatment, yet tissue hypoxia may persist because of delayed presentation, incomplete reperfusion, microvascular no-reflow, and secondary injury. Oxygen is an essential substrate for cerebral metabolism and a modifiable therapeutic exposure; however, clinical studies of oxygen-based interventions have yielded inconsistent results because of heterogeneity in timing, dose, delivery, and patient selection. Here we propose precision oxygen modulation (POM) as a stage-, phenotype-, and tissue-informed framework for the reperfusion era—treating oxygen exposure as a dose-titrated therapy that must be matched to the right patient, time window, physiological target, and safety boundary. POM integrates oxygen conditioning strategies that may prime neurovascular resilience before or around ischemia, time-limited therapeutic oxygen strategies deployed around reperfusion to support tissue at risk, and recovery-stage strategies paired with rehabilitation. We synthesize clinical and preclinical evidence linking oxygen tension to excitotoxicity, oxidative stress, inflammation, endothelial dysfunction, blood–brain barrier (BBB) integrity, and repair, while emphasizing the context-dependent risks of hyperoxia. We outline an operational decision framework and translational roadmap based on phenotype- and imaging-guided selection, biomarker validation, protocolized dosing, predefined safety boundaries, and phenotype-enriched randomized trials. POM is presented as a testable translational framework for organizing heterogeneous evidence and guiding the prospective validation of stage-specific oxygen modulation in modern stroke care.