ADAR RNA editing for cardiovascular disease: Targeting B4GALT1 to modulate lipid metabolism through reduced galactosyltransferase activity.

Cardiovascular disease remains a leading cause of mortality despite current therapies targeting low-density lipoprotein cholesterol (LDL-C). Beta-1,4-galactosyltransferase 1 (B4GALT1), a central glycosyltransferase enzyme that regulates lipoprotein metabolism and hemostasis, is a promising therapeutic target. To evaluate its therapeutic potential as a protective variant, B4galt1 p.Asn352Ser was introduced into the ribonucleic acid (RNA) of healthy wild-type and APOE∗3-Leiden.CETP transgenic mice, a well-established model for hyperlipidemia with a humanized lipoprotein metabolism, using editing oligonucleotides and the endogenous adenosine deaminases acting on RNA enzymes. The impact on hepatic glycosylation and systemic lipid homeostasis was investigated using multi-omics profiling. Editing of B4galt1 messenger RNA (∼9%-18%) resulted in substantial reductions in total cholesterol (-61%), apolipoprotein B (-72%), LDL-C (-30%), fibrinogen (-55%) (all p < 0.05), and triglycerides (-28%; p > 0.05), without altering B4galt1 expression. Proteomics of plasma and liver identified early suppression of lipogenesis and lipoprotein assembly, followed by sustained suppression of cholesterol biosynthesis and coagulation pathways. Glycomic analysis revealed remodeling of circulating glycoprotein architecture, consistent with altered B4GALT1 activity. Transcript-protein concordance was strongest in lipid pathways, while glycosylation and coagulation showed domain-specific regulatory patterns. These findings support targeting B4GALT1 using RNA editing to reduce cardiometabolic risk.