Introduction: The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer’s disease (AD) and identify potential novel targets for AD therapy. Method: Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aβ protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aβ25–35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells. Results: The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aβ and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells. Conclusions: LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells.

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