CircKif26b restoration rescues age‑related impairment of angiogenesis by stabilizing MOB4 and suppressing the Hippo pathway

Aging induces endothelial cellular senescence and leads to impaired angiogenesis. Epigenetic alterations are hallmark features of cellular senescence, and noncoding RNAs (ncRNAs) play critical roles in epigenetic regulation. However, the specific roles of circular RNAs (circRNAs) in aging endothelial cells (ECs) and impaired angiogenesis remain largely unknown. In this study, transcriptome sequencing and quantitative analysis revealed that circKif26b expression was significantly decreased in aged arteries from both mice and humans. An acute hindlimb ischemia model was established in aged mice overexpressing circKif26b to investigate its potential role as a therapeutic angiogenic target. RNA pulldown and RNA immunoprecipitation assays were performed to elucidate the mechanism by which circKif26b exerts its effects, specifically through interaction with the Mps-one-binder family member MOB4. Mechanistically, circKif26b stabilized MOB4 by preventing its ubiquitin-mediated degradation. Importantly, the circKif26b–MOB4 complex regulated angiogenic activity in ECs via the Hippo pathway by decreasing the phosphorylation of MST1/2 and YAP1 . Overall, our findings demonstrate that circKif26b downregulation with aging contributes to reduced angiogenic capacity in ECs. By stabilizing MOB4 and modulating Hippo signaling, circKif26b emerges as a potential therapeutic target for treating age-related hindlimb ischemia.