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 owing to their interactions with DNA, RNA, microRNAs, and proteins, which positions them to be 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 was induced by inflammatory stimulation, localized to the cytoplasm, and exerted regulatory effects on chemokine expression and macrophage chemotaxis. Mechanistically, SPANXA2-OT1 acted as a molecular sponge for microRNA-338, thereby influencing the expression of 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.
Authors
- Cairo Lúcio Nascimento (ORCID: https://orcid.org/0000-0002-2418-0320)
- Mary C. Whelan (ORCID: https://orcid.org/0000-0002-0139-5572)
- Shizuka Uchida (ORCID: https://orcid.org/0000-0003-4787-8067)
- Aatira Vijay
- Sasha A. Singh (ORCID: https://orcid.org/0000-0003-0929-3164)
- Thanh-Dat Le
- Sarvesh Chelvanambi (ORCID: https://orcid.org/0000-0001-9621-0704)
- Lucas Yuji Umesaki Itto (ORCID: https://orcid.org/0000-0002-2377-9884)
- Daijiro HOSOKAWA
- Dakota Becker-Greene (ORCID: https://orcid.org/0000-0003-0344-8591)
- Adrien Lupieri (ORCID: https://orcid.org/0000-0002-9245-0169)
- Elena Aïkawa (ORCID: https://orcid.org/0000-0001-7835-2135)
- Masanori Aikawa (ORCID: https://orcid.org/0000-0002-9275-2079)
- Taku Kasai (ORCID: https://orcid.org/0000-0002-8075-6099)
- Miguel Cantadori Barbeiro (ORCID: https://orcid.org/0000-0002-8856-4235)
- Prabhash Kumar Jha
- Yuto Nakamura (ORCID: https://orcid.org/0009-0001-7909-8674)
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Center for Vascular Biology Research (US)
- Aalborg University (DK)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-10-09
- DOI
- https://doi.org/10.1172/jci.insight.191274
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Brigham and Women's Hospital
- National Institutes of Health
- National Heart, Lung, and Blood Institute