SPANXA2-OT1 promotes macrophage chemotaxis

Coronary artery disease (CAD) remains the leading global cause of death, with macrophages playing a central role in driving inflammation through cytokines, chemokines, and other mediators. Using gene expression meta-analysis and weighted gene co-expression network analysis (WGCNA) of human CAD datasets, we identified 26 lncRNA–mRNA modules and prioritized SPANXA2-OT1 as a key inflammation regulator. Conservation analysis revealed SPANXA2-OT1 to be primate-specific, necessitating human macrophage models derived from PBMCs. IL-1β stimulation induced cytoplasmic SPANXA2-OT1, and antisense oligonucleotide-mediated silencing reduced chemotaxis signatures, validated by RNA-seq and proteomics. Mechanistically, SPANXA2-OT1 directly bound miR-338, as shown by luciferase assays, thereby regulating IL-8 and related chemokines critical for monocyte recruitment. CRISPR/Cas9 deletion of exon 3 further confirmed reduced IL-8 expression and impaired macrophage chemotaxis. Collectively, these findings establish SPANXA2-OT1 as a human-specific regulator of macrophage-driven inflammation in CAD and highlight its promise as a translational biomarker and therapeutic target.