Emerging Epigenetic Therapies for the Treatment of Cardiac Fibrosis

Abstract

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation.

Keywords: epigenetic; fibroblast activation; fibrosis; heart; therapies.

Figure 1

Epigenetic regulation in CVD. The complex interaction between DNA methyltransferases (DNMT), tet methylcytosine dioxygenases (TET) (DNA methylation), histone methyltransferases (HMT), histone demethylases (HDM), histone deacetylases (HDAC), histone acetyltransferases (HAT), bromodomain (Histone modifications) and ISWI, CHD, SWI/SNF, INO80 complexes (Chromatin remodeling), govern methylation (Me) of DNA and histones, acetylation (Ac) of histones, and changes in nucleosomes, consequently impacting the regulation of cardiac development, homeostasis and disease. This figure was created with Procreate (version 5.3.15).

Figure 2

Epigenetic drugs targeting cardiac fibrosis. Epigenetic modifications regulate fibroblast activation and ECM deposition, playing a key role in the progression of cardiac fibrosis. This figure illustrates different classes of epigenetic drugs and their molecular targets, including DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone/lysine demethylases (HDMs/KDMs), histone acetyltransferases (HATs), histone deacetylases (HDACs), bromodomains (BRD), and bromodomain and extra-terminal motif (BET) proteins. By modulating these mechanisms, epigenetic therapies hold potential for reversing or mitigating cardiac fibrosis. This figure was created with Adobe Illustrator (version 29.5).