Ferroptosis in Ischemic Stroke: Insights from Natural Product Treatment and Future Directions

Ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, critically contributes to ischemic stroke (IS) pathophysiology through iron overload, glutathione depletion, and dysregulation of the System Xc^-/GPX4 axis. This review systematically evaluates natural product-derived interventions targeting ferroptosis for IS management. A systematic search of PubMed, Web of Science, and ScienceDirect from their inception through May 22, 2026 identified 74 eligible studies. Our synthesis reveals three core mechanistic hubs: (1) restoring iron homeostasis by regulating ferritinophagy and iron transporters; (2) suppressing lipid peroxidation by targeting the ACSL4/LPCAT3 cascade and activating Nrf2/HO-1 signaling; and (3) reinforcing antioxidant defenses through upregulation of the System Xc^-/GSH/GPX4 pathway. The reviewed interventions encompass six major classes of natural products-including flavonoids, terpenoids, saponins, phenolic acids, phenylpropanoids, and alkaloids-and multi-herb formulas such as Buyang Huanwu Decoction and Naotaifang. Collectively, these agents reduce malondialdehyde (MDA) levels while elevating superoxide dismutase (SOD) and glutathione (GSH) activities in preclinical models. Crucially, we identify persistent translational bottlenecks, including poor pharmacokinetic profiles, undefined blood-brain barrier permeability, uncharacterized active constituents in herbal formulas, and a distinct lack of clinical validation. These findings establish that while natural compounds robustly inhibit ferroptosis in experimental models, bridging the translational gap requires rigorous standardization and high-quality clinical trials to fulfill their therapeutic potential.