tsRNA-5006c regulates hippocampal neurons ferroptosis to ameliorate perioperative neurocognitive disorders in aged male mice.

The aim of this research is to investigate whether ferroptosis occurs in the pathogenesis of perioperative neurocognitive disorders (PND), and to explore the function and underlying molecular mechanism of tsRNA in the regulation of ferroptosis in PND. A PND aged mice model was established and behavioral changes and ferroptosis occurrence were confirmed. The effect of ferroptosis inhibitor ferrostatin-1 (Fer-1) on PND mice was detected. tsRNA expression profile in PND mice and the effect of tsRNA on ferroptosis in vitro were perfomed. We found that anxious exploration behavior and short-term working memory was declined in PND mice compared with control mice, and the levels of S100β and IL-6 were increased. Meanwhile, hippocampal neurons of PND mice were damaged and accompanied by ferroptosis. Fer-1 can improve cognitive impairment in PND mice, as reflected by improved anxious exploration behavior and short-term working memory, and the levels of S100β and IL-6 were decreased. The expression profile of tsRNA in PND mice is disordered, and the dysregulated tsRNAs were mainly enriched in biologic functions related to neuronal development and ferroptosis. The tsRNA-5006c, identified as a pivotal player, significantly suppressed ferroptosis in primary mice neurons. This study shows for the first time that the pathophysiological process of PND is accompanied by ferroptosis of neurons, and reveals that tsRNA-5006c regulates ferroptosis of hippocampal neurons to ameliorate PND, which is of great significance for the development of new treatment strategies. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04176-3.