Iron metabolism and ferroptosis in ischemic stroke and intracerebral hemorrhage: a systematic review of mechanisms and modulation by natural products.

BACKGROUND: Iron dyshomeostasis and phospholipid peroxidation contribute to secondary brain injury after ischemic stroke and intracerebral hemorrhage. Ferroptosis links these processes, but subtype-specific mechanisms and findings on natural-product interventions remain incompletely integrated. PURPOSE: To systematically compare the iron-ferroptosis axis in ischemic stroke, cerebral ischemia-reperfusion injury, and intracerebral hemorrhage, and to evaluate pharmacological and natural-product interventions. METHODS: Eight bibliographic databases and ClinicalTrials.gov were searched from inception to July 2026. The review was reported in accordance with the PRISMA 2020 statement. Two reviewers independently screened records according to prespecified eligibility criteria. Findings were summarized descriptively by stroke subtype, ferroptosis mechanism, intervention class, and study stage. RESULTS: Ninety-four studies were included. Both stroke contexts converged on expansion of the labile iron pool, phospholipid peroxidation, and failure of ferroptosis-defense systems. Intracerebral hemorrhage was distinguished by erythrolysis and hemoglobin/heme-derived iron, whereas ischemic stroke/cerebral ischemia-reperfusion injury involved altered iron uptake, storage, release, and export during ischemia and reperfusion. Neuronal and microglial involvement was investigated most extensively, while recent studies also implicated oligodendrocytes, endothelial cells, and pericytes. The included studies evaluated 25 natural-product interventions or formulations for intracerebral hemorrhage and 14 for ischemic stroke/cerebral ischemia-reperfusion injury, including individual compounds, multicomponent phytomedicines, clinically evaluated natural-product-related agents, and nanodelivery systems. Most ferroptosis-related investigations remained preclinical, and comparison was limited by heterogeneous preparations, uncertain brain exposure, and insufficient target validation. No intervention has been clinically validated to improve stroke outcomes through ferroptosis inhibition. CONCLUSION: Ferroptosis is a well-supported preclinical component of secondary brain injury, but not yet a clinically validated therapeutic target. Translation requires subtype-adapted interventions, human-relevant models, validated target-engagement biomarkers, and chemically standardized natural products.