Epitranscriptome: A Novel Regulatory Layer during Atherosclerosis Progression

RNA modifications have recently gained great attention due to their extensive regulatory effects in a wide range of cellular networks and signaling pathways. In cardiovascular diseases (CVDs), several RNA changes, called "epitranscriptome" alterations, are found in all RNA molecules (tRNA, rRNA, mRNA, and ncRNAs). Unlike the epigenetic process, which influences the progression of atherosclerosis (AS), its transcriptional and post-transcriptional regulatory mechanisms are still unknown. Here, we described the main epitranscriptome signs to provide new insights into AS, including m⁶A, m⁵C, m1A, m⁷G, Ψ, and A-to-I editing. Moreover, we also included all current known RNAmodifier- targeting, including small molecular inhibitors or activators, mainly designed against m⁶A- and m⁵A-related enzymes, such as METTL3, FTO, and ALKBH5. Finally, since only a few drugs, such as azacitidine and tazemetostat, targeting the DNA epigenome, have been approved by the FDA, the next challenge would be to identify molecules for targeting the RNA epitranscriptome. To date, total Panax notoginseng total saponin could reduce vascular hyperplasia via Wilms' tumor-associated protein-1 m⁶A-dependent. Indeed, a virtual screening allowed us to individuate a phytomolecule, the rhein, which acts as an FTO inhibitor by increasing mRNA m⁶A levels. In this review, we highlighted the RNA epitranscriptome pathways implicated in AS, describing their biological functions and their connections to the disease. The identification of epitranscriptome- sensitive pathways could provide novel opportunities to find predictive, diagnostic, and prognostic biomarkers for precision medicine.