LncRNA NEAT1 Knockdown Alleviates Macrophage Ferroptosis and Atherosclerosis by Suppressing STAT3 Activation.

Background: This study aimed to investigate the role and mechanism of long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) in macrophage ferroptosis during atherosclerosis (AS). Methods: The clinical characteristics and disease severity were assessed in 84 patients with coronary heart disease (CHD). The role of NEAT1 in high-fat diet-induced AS and the impact of exercise were examined in APOE-/- and NEAT1-/- mice. Human monocyte THP-1 cells were utilized to explore cellular mechanisms underlying AS. Quantitative real-time PCR, immunofluorescence staining, and Western blot analysis were employed to analyze gene expression. Transmission electron microscopy and fluorescence in situ hybridization were used to examine cellular and tissue-level changes. Bioinformatics analyses were conducted to explore protein interactions and functional networks. Results: NEAT1 expression and iron levels were correlated with disease severity in CHD patients. In THP-1 cells, oxidized low-density lipoprotein (ox-LDL) induced NEAT1 expression, ferroptosis marker ACSL4, reactive oxygen species (ROS), and mitochondrial abnormalities. Knockdown of NEAT1 reversed these effects. NEAT1 overexpression increased pSTAT3, ACSL4, and ROS production, reversed by STAT3 inhibitor. NEAT1 physically interacted with STAT3 via FBXW11. Knockdown of NEAT1 promoted pSTAT3 ubiquitination, reduced ACSL4 expression, and reversed ox-LDL effects. NEAT1 deletion attenuated macrophage ferroptosis and AS in APOE-/- mice. Exercise reduced NEAT1 and ferroptosis indicators in mice and CHD patients. Conclusions: NEAT1 plays a crucial role in macrophage ferroptosis during AS. Targeting NEAT1 or exercising may provide therapeutic interventions against AS.