<p>This study aims to investigate the expression of circLOC375190 in stroke and its impact on neuronal mitochondrial dysfunction, ferroptosis, and the molecular pathways involved.&#xa0;We utilized bioinformatics tools, including the GEO database (GSE133768), to identify differentially expressed circRNAs in stroke. The expression levels of circLOC375190 were validated. siRNA-mediated knockdown of circLOC375190 was performed, followed by assessments of cell viability, mitochondrial membrane potential, ROS levels, ATP production, and ferroptosis markers. Interaction studies between circLOC375190 and the RNA-binding protein IGF2BP2 were performed. The effect of circLOC375190 on IGF2BP2-mediated regulation of HUWE1 mRNA stability was examined. The therapeutic potential of circLOC375190 knockdown was evaluated in an MCAO/R mouse model.&#xa0;circLOC375190 was significantly upregulated in both MCAO/R mouse brain tissues and OGD/R-treated SH-SY5Y cells. Knockdown of circLOC375190 in OGD/R-treated SH-SY5Y cells improved cell viability, mitochondrial function, and reversed signs of ferroptosis. Knockdown of circLOC375190 alleviated mitochondrial dysfunction. Knockdown of circLOC375190 suppressed ferroptosis-related proteins, while enhancing the expression of protective factors like Ferritin and GPX4. circLOC375190 interacted with IGF2BP2, a known regulator of stroke progression. Overexpression of circLOC375190 promoted the ubiquitination and degradation of IGF2BP2, which in turn modulated its effects on HUWE1. In vivo, circLOC375190 knockdown reduced neuronal apoptosis and mitigated ischemia–reperfusion–induced tissue injury in MCAO/R mice, further supporting its role in stroke pathology.&#xa0;By promoting IGF2BP2 degradation and altering the stability of HUWE1 mRNA, circLOC375190 exacerbates mitochondrial dysfunction and ferroptosis in neurons.</p>