Circular RNA uridine-cytidine kinase (UCK) 2 ameliorates mitochondrial injury after cerebral ischemia reperfusion and promotes angiogenesis via modulating the microRNA-188-5p/phosphatase and tensin homolog axis.

The roles of circular RNAs (circRNAs) in the concurrent processes of mitochondrial damage and angiogenesis following cerebral ischemia-reperfusion (CI/R) injury remain largely uncharacterized. This study investigated the function of circUCK2 in CI/R and tested the hypothesis that it exerts a protective effect by modulating the miR-188-5p/phosphatase and tensin homolog (PTEN) signaling axis. In vivo middle cerebral artery occlusion/reperfusion (MCAO/R) and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models were employed. A combination of lentiviral delivery, neurological scoring, histological analysis (hematoxylin and eosin, TUNEL), RT-qPCR, Western blot, flow cytometry (apoptosis, reactive oxygen species), tube formation assays, and dual-luciferase reporter assays was used to investigate the underlying mechanisms. In CI/R models, circUCK2 and PTEN expression was significantly downregulated, while miR-188-5p was upregulated (P<0.05). Overexpression of circUCK2 in MCAO/R mice significantly ameliorated neurological deficits, attenuated neuronal apoptosis, mitigated mitochondrial oxidative stress, and promoted angiogenesis (P<0.05 for all outcomes). Mechanistically, circUCK2 was identified as a cytoplasmic sponge for miR-188-5p, which in turn was shown to directly target and suppress PTEN expression (P<0.05). Crucially, the neuroprotective and pro-angiogenic effects of circUCK2 were significantly counteracted by PTEN knockdown (P<0.05), positioning PTEN as a critical downstream mediator of circUCK2's function. We found that circUCK2 exerts a protective role against CI/R injury by sequestering miR-188-5p, thereby derepressing PTEN expression. This study identifies the circUCK2/miR-188-5p/PTEN axis as a key regulatory pathway and a promising therapeutic target for ischemic stroke.