Abstract
<title>Abstract</title> <p>Background Perioperative neurocognitive disorder (PND) is a common complication in elderly surgical patients with incompletely understood pathogenesis. Although circular RNAs (circRNAs) regulate neuroinflammation, their role in PND remains unclear. We identify a novel circRNA_29625–SIRT1 axis linking surgical stress to cognitive decline. Methods An aged mouse PND model was established via tibial fracture surgery under isoflurane anesthesia. Cognitive function (fear conditioning), SIRT1 expression (immunofluorescence, western blot), neuroinflammation (ELISA), synaptic plasticity (Golgi staining), and circRNA expression (RT-qPCR) were assessed. Stereotactic viral injections manipulated circRNA_29625 and SIRT1 in the hippocampal CA1 region. Results Anesthesia/surgery induced hippocampal neuroinflammation, reduced SIRT1, increased oxidative stress, impaired synaptic plasticity, and caused cognitive deficits. circRNA_29625 was significantly downregulated in PND mice, which was reversed by minocycline. circRNA_29625 knockdown decreased SIRT1, while overexpression rescued SIRT1 under inflammatory conditions. In vivo, overexpression of circRNA_29625 or SIRT1 alleviated synaptic impairment and cognitive dysfunction; co-overexpression with SIRT1 knockdown abrogated these protective effects. Conclusion We identify the circRNA_29625–SIRT1 axis as a novel regulatory mechanism in PND, where neuroinflammation-induced circRNA_29625 downregulation reduces SIRT1, exacerbating oxidative stress, synaptic dysfunction, and cognitive decline. This axis represents a potential therapeutic target for PND.</p>