RUNX1 silencing protects against cerebral ischemia/reperfusion injury-induced endoplasmic reticulum stress, inflammation, ferritinophagy and ferroptosis through the CELF2/mTOR axis.

PIP4K2A Attenuates Cerebral Ischemia/Reperfusion Injury by Reducing the TRIB3-p62 Complex Burden and Modulating AKT/mTOR Signaling

Knockdown of TRIM21 inhibits ferroptosis via the p62-Keap1-Nrf2 pathway thereby improving brain injury and mitochondrial dysfunction after ischemia-reperfusion in mice.

Ferroptosis has a crucial role in cerebral ischemia-reperfusion injury (IRI) but its potential modulation is a key challenge in the treatment of ischemic stroke. The function and mechanism of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) in neurological diseases, particularly its regulatory role in ferroptosis are unclear. We used a mouse model of transient middle cerebral artery occlusion (tMCAO/R) and a PC12 cell model of oxygen-glucose deprivation/reperfusion (OGD/R) to investigate the effects of virus-mediated gene knockdown of TRIM21. Effects were assessed using Western blotting, immunoprecipitation, biochemical assays, and behavioral tests. TRIM21 expression was significantly increased after cerebral IRI. Knockdown of TRIM21 improved neurological deficits, reduced cerebral infarct size, and suppressed inflammation. Knockdown of TRIM21 also inhibited ferroptosis and improved mitochondrial function whereas TRIM21 negatively regulated the p62-Keap1-Nrf2 pathway through ubiquitination of p62. Salvage experiments confirmed that Nrf2 is a key downstream molecule for the neuroprotective effects of TRIM21. The data indicate that TRIM21 inhibition of the Keap1-Nrf2 pathway through p62 ubiquitination exacerbated ferroptosis after ischemic stroke in the tMCAO/R model and suggest that targeted inhibition of TRIM21 holds promise as a novel strategy for treating ischemic stroke.

Gomisin A Attenuates Cerebral Ischemia/Reperfusion Injury Through Activation of the VEGF/PI3K/AKT/NOS3 Signaling Pathway.

Fosl2/c-Jun dimer induces oxidative stress and endoplasmic reticulum stress by enhancing Lcn2 transcription to promote ischemic cerebral infarction.

Fosl2 or c-Jun knockdown reduced cerebral infarction volume, alleviated blood-brain barrier injury, and suppressed oxidative stress and ERS, thereby contributing to ICI.

Curcumin prevents ferroptosis and shields against cerebral ischemia-reperfusion injury by modulating GPX4 H3K18ac via KLF2

Abstract Cerebral ischemia-reperfusion injury (CIRI) involves complex pathological mechanisms, including ferroptosis. Curcumin exhibits neuroprotective properties, but its role in modulating ferroptosis during CIRI remains incompletely understood. This research explored how curcumin protects against ferroptosis in CIRI and the molecular mechanisms involved. In vivo, male MCAO rats were divided into Sham, MCAO, and curcumin low/medium/high-dose groups. Infarct volume, neurological deficit scores, and ferroptosis markers (MDA, Fe2+, GSH, GPX4, FTH1, TfR1) were detected. In vitro, OGD/R-stimulated BV2 cells were administered with curcumin or Ferrostatin-1. GPX4 knockdown, KLF2, and KAT2A overexpression or knockdown were performed. ChIP, CCK-8, and western blotting were applied to identify H3K18ac modification, cell viability, and protein expression, respectively. In MCAO rats, curcumin administration led to a reduction in infarct size, better neurological outcomes, and a decrease in ferroptosis. In vitro, curcumin inhibited OGD/R-stimulated ferroptosis and enhanced H3K18 acetylation at the GPX4 promoter. Mechanistically, curcumin upregulated the transcription factor KLF2, which transcriptionally activated the histone acetyltransferase KAT2A. KAT2A mediated H3K18ac modification at the GPX4 promoter, leading to GPX4 upregulation and ferroptosis suppression. KLF2 knockdown abolished the protective effects of curcumin. In conclusion, Curcumin inhibited ferroptosis in CIRI by activating the KLF2/KAT2A/GPX4 signaling axis, highlighting a novel epigenetic mechanism and potential therapeutic strategy for ischemic stroke. HIGHLIGHTS Curcumin prevented ferroptosis in MCAO rats Curcumin enhanced GPX4 H3K18ac modification and inhibited ferroptosis KAT2A mediated GPX4 H3K18ac modification and suppressed BV2 cells ferroptosis under OGD/R conditions KLF2 transcriptionally activated KAT2A and inhibited OGD/R-stimulated BV2 cells ferroptosis By activating the KLF2/KAT2A/GPX4 axis, curcumin prevented ferroptosis in BV2 cells subjected to OGD/R.

CircRNA_0004468 promotes VEGFA-mediated neurovascular repair by sponging miR-1224 in remote ischemic postconditioning against cerebral ischemia-reperfusion injury.

BACKGROUND Cerebral ischemia/reperfusion injury remains a major barrier to neurological recovery after recanalization therapy. Although remote ischemic postconditioning (RIPostC) has neuroprotective potential, its non-coding RNA mechanisms remain unclear. This study investigated whether the circular RNA 0004468 (circRNA_0004468)/microRNA-1224 (miR-1224)/vascular endothelial growth factor A (VEGFA) axis mediates RIPostC-induced protection against cerebral ischemia/reperfusion injury. METHODS Oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells were used as an in vitro model of ischemia-reperfusion injury, whereas rats subjected to ischemia/reperfusion (I/R), with or without RIPostC, were used for in vivo validation. The expression of circRNA_0004468, miR-1224, VEGFA, and PI3K-related proteins was examined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Cell viability, apoptosis, molecular interactions, infarct volume, histopathological injury, neurological deficits, and endothelial repair were evaluated using Cell Counting Kit-8 (CCK-8) assay, flow cytometry, fluorescence in situ hybridization, dual-luciferase reporter assay, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin staining, behavioral scoring, and immunofluorescence staining. RESULTS OGD/R decreased circRNA_0004468 and VEGFA expression but increased miR-1224 expression in PC12 cells. CircRNA_0004468 overexpression or miR-1224 inhibition improved cell viability and reduced apoptosis after OGD/R. Mechanistically, circRNA_0004468 directly bound to miR-1224 and relieved miR-1224-mediated suppression of VEGFA. In MCAO/R rats, RIPostC upregulated circRNA_0004468 and VEGFA, downregulated miR-1224, reduced infarct volume, alleviated neuronal injury, enhanced CD31 and CD34 expression, and improved neurological outcomes. These protective effects were further strengthened by circRNA_0004468 overexpression, miR-1224 inhibition, or VEGFA overexpression. CONCLUSIONS The circRNA_0004468/miR-1224/VEGFA axis contributes to RIPostC-mediated neurovascular protection and may represent a potential target for improving recovery after ischemic stroke.