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. 2025 Jan;15(1):16.
doi: 10.1007/s13205-024-04176-3. Epub 2024 Dec 18.

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

Chuanlin Zhou  1 , Fang Lian  2 , Hejian Li  2 , Fumou Deng  2
Affiliations

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

Chuanlin Zhou et al. 3 Biotech. 2025 Jan.

Abstract

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.

Keywords: Ferroptosis; Hippocampus; Neuron; Perioperative neurocognitive disorders; tsRNA-5006c.

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Conflict of interest statement

Conflict of interestThe authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Experimental flow chart of this study. PND perioperative neurocognitive disorders, Fer-1 Ferrostatin-1
Fig. 2
Fig. 2
Behavioral tests showed decreased memory and learning in PND mice. A Images of open field test results of mice in sham group and PND group from day 5–8 and statistical analysis of immobility time were performed. B Images of Y-Maze test results of mice in sham group and PND group from day 5–8 and statistical analysis of correct rate of spontaneous alternation. C The levels of S100β and IL-6 in serum of sham and PND mice were detected by enzyme-linked immunosorbent assay (ELISA). D The levels of S100β and IL-6 in serum of sham and PND mice were detected by western blot (WB). *p < 0.05, **p < 0.01, n = 3 or 5
Fig. 3
Fig. 3
Ferroptosis occurs in neurons in the hippocampus of PND mice. A Nissl staining of hippocampal tissue neurons from sham and PND mice on day 9. Scale = 50 μm. B WB was used to detect the expression of GPX4 and FTH1. C Fe2+ and malondialdehyde (MDA) were detected by kit. D IF detection of GPX4 and GFAP colocalization. Scale = 50 μm. E Co-localization of GPX4 and NeuN detected by IF. Scale = 50 μm. *p < 0.05, **p < 0.01, n = 3 or 5
Fig. 4
Fig. 4
Inhibit ferroptosis improve cognitive impairment of mice. A Images of open field test results of mice in PND + vehicle group and PND + Fer-1 group from day 5–8 and statistical analysis of immobility time were performed. B Images of Y-Maze test results of mice in PND + vehicle group and PND + Fer-1 group from day 5–8 and statistical analysis of correct rate of spontaneous alternation. C The levels of S100β and IL-6 in serum of mice were detected by ELISA. D The levels of S100β and IL-6 were detected by WB. E Fe2+ and MDA levels were detected by kit. F Nissl staining of hippocampal tissue neurons from PND + vehicle and PND + Fer-1 mice on day 9. Scale = 50 μm. *p < 0.05, **p < 0.01, n = 3 or 5
Fig. 5
Fig. 5
tsRNA expressed in the bioinformatics analysis of sham vs PND. A Radar plot showing tsRNA expression profile. B Top 20 of GO enrichment based on the target genes of differentially expressed tsRNAs. C Top 20 of pathway enrichment based on the target genes of differentially expressed tsRNAs. D tsRNA-KEGG-GO network diagram
Fig. 6
Fig. 6
tsRNA-5006c inhibits neuronal cell ferroptosis. A tsRNA expression by small RNA-seq. B q-PCR verify differentially expressed tsRNA. C The transfection efficiency of tsRNA-5006c mimics was detected by q-PCR. D The expression of GPX4 and FTH1 in NC and tsRNA-5006c mimics was detected by WB. E Fe2+ and MDA levels in NC and tsRNA-5006c mimics were detected by kits. *p < 0.05, **p < 0.01, n = 3
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