Astragaloside IV as a Multi-Target Neuroprotective Candidate in Ischemic Stroke and Cerebral Ischemia-Reperfusion Injury: Molecular Mechanisms and Therapeutic Perspectives

Ischemic stroke (IS) and cerebral ischemia-reperfusion injury (CIRI) involve overlapping but temporally distinct pathological processes, including oxidative stress, neuroinflammation, regulated cell death, impaired neurovascular repair, and systemic risk-factor regulation. Astragaloside IV (AS-IV), a major active saponin from Astragalus membranaceus, has attracted attention as a multi-target neuroprotective candidate. This narrative review critically evaluates the molecular mechanisms, preclinical evidence, translational limitations, and potential delivery strategies relevant to AS-IV in IS and CIRI. PubMed, Web of Science, Scopus, and Google Scholar were searched using combinations of terms related to AS-IV, ischemic stroke, cerebral ischemia-reperfusion injury, oxidative stress, neuroinflammation, pyroptosis, ferroptosis, apoptosis, autophagy, neurogenesis, angiogenesis, blood-brain barrier, pharmacokinetics, and drug delivery. Original in vivo and in vitro studies, mechanistic reports, pharmacokinetic studies, and clinically relevant translational literature were prioritized. During revision, the literature base was updated through August 2026, and approximately 90 publications were retained for the final narrative synthesis. Preclinical evidence indicates that AS-IV may modulate ROS/Nrf2-related antioxidant signaling, cytokine networks, microglia/macrophage polarization, NK-cell infiltration, NLRP3-mediated pyroptosis, FTO/m6A/ACSL4- and p62/KEAP1/Nrf2-related ferroptosis, intrinsic and extrinsic apoptosis, context-dependent autophagy/mitophagy, neurogenesis, angiogenesis, and blood-pressure-related mechanisms. However, reported effects vary across models, doses, routes, treatment windows, and outcome measures. Quantitative pharmacokinetic studies further indicate low oral bioavailability and limited brain distribution, which constrain direct clinical extrapolation. AS-IV shows broad preclinical activity across several IS/CIRI-related mechanisms, but the current evidence base remains dominated by cellular and animal studies. Clinical translation is limited by low oral bioavailability, restricted blood-brain barrier penetration, uncertain effective brain exposure, route- and dose-dependent safety considerations, heterogeneous experimental models, and the absence of high-quality randomized controlled trials in IS/CIRI. AS-IV should therefore be considered an investigational adjunctive neuroprotective candidate rather than a substitute for established recanalization therapies. Future work should prioritize reproducible pharmacokinetic/pharmacodynamic validation, standardized preclinical designs, brain-targeted delivery systems, and carefully timed adjunctive clinical studies.