Cardiovascular diseases (CVDs) remain as the leading global health challenge, responsible for the highest mortality rates worldwide and imposing significant socioeconomic burdens on healthcare systems (Conrad et al., 2025). Despite progress in conventional therapies that has decreased mortality from acute cardiovascular events, enduring challenges remain: high rates of chronic complications, complex pathological networks involving inflammation, metabolic dysregulation, and extracellular matrix remodeling, as well as significant interindividual variability in treatment responses. This variability is influenced by genetic and epigenetic heterogeneity. This therapeutic gap highlights the necessity of investigating new regulatory mechanisms, particularly dynamic epigenetic reprogramming—an essential link between environmental factors and gene expression that does not alter DNA sequences (Mao et al., 2024). In this context, reversible RNA modifications are crucial regulators of cardiovascular pathogenesis, dynamically controlling RNA stability, translation, splicing, and subcellular localization to finely tune critical cardiovascular biological processes (Gatsiou and Stellos, 2022).

The METTL family, comprising evolutionarily conserved enzymes with SAM-binding domains, serves as pivotal regulators of epitranscriptomic modifications (Zhang et al., 2024). These enzymes display distinct substrate specificity across various molecular targets, orchestrating essential cellular processes such as RNA metabolism, mitochondrial bioenergetics, and stress adaptation through precise catalytic activities. Dysregulation of METTL proteins is mechanistically linked to cancer, neurodegenerative disorders, and notably complex cardiovascular pathologies, ranging from arrhythmias to pulmonary hypertension (He et al., 2024).

This review systematically summarizes the mechanistic roles of METTL-driven methylation networks in cardiovascular diseases, including myocardial infarction, maladaptive cardiac remodeling, atherosclerosis, and arrhythmogenesis. We focus on their regulation of key cellular phenotypes, tissue remodeling processes, and metabolic-inflammatory cascades. Furthermore, we critically evaluate the clinical translational potential of METTL members as diagnostic/prognostic biomarkers and therapeutic targets, while addressing current research limitations and future directions. By integrating recent advances in epitranscriptomics and cardiovascular biology, we aim to provide a comprehensive framework for understanding METTL-mediated epigenetic regulation and its implications for precision medicine in CVDs.