Simple SummaryDyslipidemia is a significant risk factor for cardiovascular disease, and current treatments such as statins can have toxic side effects. RCI-1502, a bioproduct derived from the EuropeanS. pilchardus, has shown potential as a natural and less toxic alternative treatment for cardiovascular disorders. Alterations in DNA methylation patterns may contribute to the development and progression of lipid metabolism disorders, including atherosclerosis and other cardiovascular diseases. Alterations in DNA methylation may contribute to the development and progression of lipid metabolism disorders, including atherosclerosis and other cardiovascular disorders. In this study, we conducted proteomic analysis of RCI-1502 extracts and classified the identified proteins by their primary molecular functions using the PANTHER classification system. We furthermore investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in a high-fat diet mouse model and in patients with lipid metabolism disorders. RCI-1502 treatment regulated the expression of cardiovascular-related genes and reduced DNA methylation levels in both the high-fat diet model and human samples. Furthermore, RCI-1502 regulated cholesterol and triglyceride levels in dyslipidemic patients. Our findings suggest that RCI-1502 is an epigenetic modulator with promising therapeutic potential for dyslipidemia and associated cardiovascular disorders and highlight the potential of epigenetic modulators in treating lipid metabolism disorders. Future studies could explore the combination of RCI-1502 with established treatments for dyslipidemia.AbstractDyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.