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Cardiac mesoderm enhancer-associated non-coding RNA (CARMN), an evolutionarily conserved long non-coding RNA (lncRNA), serves as the host gene for the miR143/145 cluster. It plays a crucial role in cardiovascular cell differentiation and the maintenance of vascular smooth muscle cell (VSMC) homeostasis, which are vital for normal physiological processes. Specifically, CARMN is associated with the pathological progression of cardiovascular diseases such as atherosclerosis, abdominal aortic aneurysm, and chronic heart failure. Moreover, it acts as a tumor suppressor in various cancers, including hepatocellular carcinoma, bladder cancer, and breast cancer, highlighting its potential as a beneficial biomarker and therapeutic target. This review provides a detailed examination of the roles of CARMN, its evolutionary conservation, expression patterns, and regulatory mechanisms. It also outlines its significant implications in the diagnosis, prognosis, and treatment of these diseases, underscoring the need for further translational research to exploit its clinical potential.

Fibrotic liver features excessive deposition of extracellular matrix (ECM), primarily produced from “activated” hepatic stellate cells (HSCs). While targeting human HSCs (hHSCs) in fibrosis therapeutics shows promise, the overall understanding of hHSC activation remains limited, in part because it is very challenging to define the role of human long non-coding RNAs (lncRNAs) in hHSC activation. To address this challenge, we identified another cell type that acts via a diverse gene network to promote fibrogenesis. Then, we identified the lncRNAs that were differentially regulated in activated hHSCs and the other profibrotic cell. Next, we conducted concurrent analysis to identify those lncRNAs that were specifically involved in fibrogenesis. We tested and confirmed that transdifferentiation of vascular smooth muscle cells (VSMCs) represents such a process. By overlapping TGFβ-regulated lncRNAs in multiple sets of hHSCs and VSMCs, we identified a highly selected list of lncRNA candidates that could specifically play a role in hHSC activation. We experimentally characterized one human lncRNA, named CARMN, which was significantly regulated by TGFβ in all conditions above. CARMN knockdown significantly reduced the expression levels of a panel of marker genes for hHSC activation, as well as the levels of ECM deposition and hHSC migration. Conversely, gain of function of CARMN using CRISPR activation (CRISPR-a) yielded the completely opposite effects. Taken together, our work addresses a bottleneck in identifying human lncRNAs that specifically play a role in hHSC activation and provides a framework to effectively select human lncRNAs with significant pathophysiological role.