A systems approach to target discovery identifies the role of lncRNA-SPANXA2-OT1 in macrophage chemotaxis.

Coronary artery disease (CAD) is the leading cause of mortality worldwide, with macrophages playing a central role in shaping the inflammatory environment through cytokines, chemokines, and other mediators. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular processes due to their interactions with DNA, RNA, microRNAs, and proteins, positioning them as promising therapeutic targets. Through integrative transcriptomic analysis, we identified SPANXA2-OT1 as a primate-specific lncRNA with a potential role in macrophage-mediated inflammation in CAD. Functional studies in primary human macrophages demonstrated that SPANXA2-OT1 is induced by inflammatory stimulation, localized to the cytoplasm, and exerts regulatory effects on chemokine expression and macrophage chemotaxis. Mechanistically, SPANXA2-OT1 acts as a molecular sponge for microRNA-338, thereby influencing the expression of interleukin-8 (IL-8), a critical mediator of monocyte recruitment and inflammatory signaling. Collectively, these findings establish SPANXA2-OT1 as a human-specific regulator of inflammatory pathways in CAD and highlight its translational potential as both a biomarker and therapeutic target.