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Due to the complex pathogenesis of acute ischemic stroke (AIS), further investigation into its underlying mechanisms is necessary. Presently, existing literature indicates a close association between ferroptosis and AIS injury; however, the precise mechanism and molecular target of ferroptosis in AIS injury remain elusive. By RNA sequencing, we found a significant increase in LCN2 expression in the ischemic cortex. In order to investigate the potential role of LCN2 in modulating AIS injury through the regulation of ferroptosis, we utilized RNA interference (RNAi) knockdown and gene overexpression experiments. The findings from experiments conducted both in vitro and in vivo revealed a marked increase in ferroptosis levels within the AIS model group. Suppression of the LCN2 gene resulted in a significant reduction in ferroptosis levels in OGD/R cells. Conversely, upregulation of LCN2 exacerbated ferroptosis levels in OGD/R cells. The results suggest that elevated levels of ferroptosis may result from heightened expression of LCN2, thereby exacerbating ischemia/reperfusion injury. This study indicates the involvement of ferroptosis in the pathogenesis of AIS and highlights LCN2 as a regulator of ferroptosis in AIS-induced injury, suggesting a potential therapeutic target for ischemic stroke., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As the main bioactive component of musk, muscone has been reported to have marked protective effects in treating acute ischemic stroke (AIS). However, the specific anti-stroke mechanism of muscone still needs further research. In the current investigation, the PC12 cells OGD/R and the rat transient MCAO/R models were utilized as the AIS models. Serum hepatic and renal functional indexes (ALT, AST, BUN, and Cr) and cell viability were determined to select the appropriate muscone concentrations for in vitro and in vivo experiments. TTC, Hematoxylin and eosin (H&E), and Live/Dead staining were utilized to evaluate the protective effects of muscone in injured tissues and cells. Western blotting analysis, TUNEL staining, propidium iodide, and annexin V staining were applied to detect the anti-apoptotic effect of muscone. Double-label immunofluorescence staining of T-cell intracellular antigen-1 (TIA1) and Ras-GAP SH3 domain-binding protein 1 (G3BP1) was performed to observe whether muscone regulated the SG formation level. Molecular docking, TIA1 silencing and TIA1 overexpression experiments were employed to investigate the molecular mechanism underlying the regulation of SG formation by muscone. The 2, 3, 5-Triphenyl-tetrazolium chloride (TTC) staining and live/dead staining showed the AIS injury level of MCAO/R rat and the OGD/R PC12 cells were attenuated by muscone administration. The muscone significantly minimized the apoptosis rate in MCAO/R rats and OGD/R PC12 cells following flow cytometry analysis, western blotting analysis, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The double-label immunofluorescence staining data revealed that muscone promoted the SG formation level in OGD/R PC12 cells and the cortex MCAO/R rats. The results of molecular docking, TIA1 silencing and TIA1 overexpression experiments revealed that muscone could bind to TIA1 protein and regulate its expression level, thereby promoting the formation of stress granules and exerting a protective effect against AIS injury. This study indicated that the significant protective effect of muscone in reducing apoptosis levels might be via promoting SG formation under AIS conditions. This study further explores the therapeutic effect and anti-apoptosis mechanism of muscone in AIS, which may provide a potential candidate drug for the clinical treatment of AIS injury., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of commercial interest or competition in this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Due to the limited clinical treatment options for acute ischemic stroke (AIS), there is still an urgent requirement for in-depth research on the pathogenesis of AIS and the development of efficient therapeutic approaches and agents. Literature reports reveal that ferroptosis may play an important role in the pathogenesis of AIS. However, the specific mechanism and the molecular target of action of ferroptosis in AIS injury remains unclear. In this study, we constructed AIS rat and PC12 cell models. We applied RNAi-mediated knockdown and gene overexpression technologies to investigate whether Snap25 (Synaptosome-associated protein 25 kDa) can regulate the level of AIS damage by interfering with the level of ferroptosis in AIS. The in vivo and in vitro results revealed that the level of ferroptosis significantly increased in the AIS model. Snap25 gene overexpression significantly inhibited the ferroptosis level and decreased the AIS damage and OGD/R injury level in the model group. Snap25 silencing exacerbated the ferroptosis level and aggravated OGD/R injury in PC12 cells. The overexpression and silencing of Snap25 can significantly affect the expression level of ROS, suggesting that the regulatory effect on the ROS level may be an important factor in regulating ferroptosis in AIS by Snap25. In conclusion, the findings of this study suggested that Snap25 has a protective effect against ischemia/reperfusion injury by reducing ROS levels and ferroptosis levels. This study further confirmed the involvement of ferroptosis in the process of AIS injury and explored the regulatory mechanism of Snap25 on the ferroptosis level in AIS, which could provide a promising therapeutic target for ischemic stroke treatment., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)