Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in the complex pathophysiology of ischemic stroke, a leading cause of global death and disability. This review synthesizes current understanding of the core ferroptosis pathways, including iron dysregulation, glutathione depletion, and GPX4 inactivation and distinguishes it from other cell death modalities. We critically explore its role as a pathogenic amplifier in stroke, synergizing with neuroinflammation and mitochondrial dysfunction to expand neuronal injury. The review systematically assesses therapeutic strategies, from iron chelators and lipid peroxidation inhibitors (e.g., ferrostatin-1) to emerging gene therapies and nanomedicine-based approaches, based on robust preclinical evidence. However, translating these findings faces challenges, including a narrow therapeutic window, patient heterogeneity, and the need to balance efficacy with safety concerning systemic iron and lipid metabolism. To overcome these translational challenges, future research must prioritize the discovery of clinical biomarkers (e.g., FABP5) and the development of targeted delivery systems to advance ferroptosis-directed therapies for stroke.

Numerous studies have demonstrated that genes, RNAs, and proteins are involved in the occurrence and development of stroke. In addition, previous studies concluded that microRNAs (miRNAs or miRs) are closely related to the pathological process of ischemic and hypoxic disease. Therefore, the aims of this study were to quantify the altered expression levels of miRNAs in the infarct region 6 h after middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in mice using a large-scale miRNAs microarray. Firstly, MCAO-induced cerebral ischemic injuries were investigated by observing the changes of neurological deficits, infarct volume and edema ratio. One hundred and eighteen differentially expressed miRNAs were identified in the infarct region of mice following the MCAOs compared with sham group (p < 0.05 was considered as significant). Among these 118 significantly expressed microRNAs, we found that 12 miRNAs were up-regulated with fold changes lager than two, and 18 miRNAs were down-regulated with fold changes less than 0.5 in the infarct region of mice following the 6 h MCAOs, compared with the sham group. Then, these 30 miRNAs with expression in fold change larger than two or less than 0.5 was predicted, and the functions of the target genes of 30 miRNAs were analyzed using a bioinformatics method. Finally, the miRNA-gene network was established and the functional miRNA-mRNA pairs were identified, which provided insight into the roles of the specific miRNAs that regulated specified genes in the ischemic injuries. The miRNAs identified in this study may represent effective therapeutic targets for stroke, and further study of the role of these targets may increase our understanding of the mechanisms underlying ischemic injuries.

Objective: Remote limb ischemic postconditioning (RIPostC) protects the brain from damage induced by transient focal ischemia/reperfusion. However, the underlying mechanism remains unclear. Methods: RIPostC induced by 10 min of occlusion and another 10 min releasing of blood flow for three cycles in the hind limbs was performed immediately after the reperfusion in a focal ischemia mice model. Neurological scores, immune cell population in the blood, spleen and lymph node, and inflammatory factors in the blood and brain were analyzed 2 days after the reperfusion. Results: Our results demonstrate that RIPostC reduced cerebral injuries and improved neurological functions 2 days after reperfusion. RIPostC significantly inhibited the reduction in the percentage of CD4 T cells in the spleen and lymph node, CD8 T cells in the blood and lymph node, and natural killer T (NKT) cells in the spleen by flow cytometry analysis. RIPostC attenuated the increase of B cells and NK cells in the spleen and noninflammatory monocytes in the blood. The cytokine assay showed that RIPostC decreased the elevation of IL-10, IL-6, and TNF-α in the blood after ischemia. The quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) results indicated that the mRNA level of IL-4 in the brain increased in the middle cerebral artery occlusion mice after RIPostC treatment. Conclusions: The present study indicates that there were significant changes of inflammatory responses during the neuroprotection induced by RIPostC in stroke mice.