*Review* **The Function and Therapeutic Potential of lncRNAs in Cardiac Fibrosis**

**Xiang Nie 1,2, Jiahui Fan 1,2 and Dao Wen Wang 1,2,\***


**Simple Summary:** Cardiac fibrosis is a vital pathophysiologic change in heart disease, which eventually leads to heart failure. Several molecular mechanisms positively or negatively regulate myocardial fibrosis, among which long noncoding RNAs have gained increased attention. We summarize the contributions of lncRNAs to miRNA expression, TGF-β signaling, and ECMs synthesis, with a particular attention on the exosome-derived lncRNAs in the regulation of adverse fibrosis as well as the mode of action of lncRNAs secreted into exosomes. We also discuss how the current knowledge on lncRNAs can be applied to develop novel therapeutic strategies. This study may provide clues for the prevention and therapy of cardiac fibrosis.

**Abstract:** Cardiac fibrosis remains an unresolved problem in cardiovascular diseases. Fibrosis of the myocardium plays a key role in the clinical outcomes of patients with heart injuries. Moderate fibrosis is favorable for cardiac structure maintaining and contractile force transmission, whereas adverse fibrosis generally progresses to ventricular remodeling and cardiac systolic or diastolic dysfunction. The molecular mechanisms involved in these processes are multifactorial and complex. Several molecular mechanisms, such as TGF-β signaling pathway, extracellular matrix (ECM) synthesis and degradation, and non-coding RNAs, positively or negatively regulate myocardial fibrosis. Long noncoding RNAs (lncRNAs) have emerged as significant mediators in gene regulation in cardiovascular diseases. Recent studies have demonstrated that lncRNAs are crucial in genetic programming and gene expression during myocardial fibrosis. We summarize the function of lncRNAs in cardiac fibrosis and their contributions to miRNA expression, TGF-β signaling, and ECMs synthesis, with a particular attention on the exosomederived lncRNAs in the regulation of adverse fibrosis as well as the mode of action of lncRNAs secreted into exosomes. We also discuss how the current knowledge on lncRNAs can be applied to develop novel therapeutic strategies to prevent or reverse cardiac fibrosis.

**Keywords:** cardiac fibrosis; lncRNAs; TGF-β; ECMs; exosome
