Collagen Hydroxylysine Glycosylation in Cardiac Fibrosis: Mechanisms, Enzymes and Therapeutic Opportunities

Cardiac fibrosis is usually described as a problem of excessive extracellular matrix production, yet collagen abundance alone does not explain why some fibrotic matrices become unusually persistent, stiff and resistant to regression. Fibrillar collagens undergo an extensive sequence of post-translational modifications before they enter the extracellular matrix. Among these, O-linked glycosylation of hydroxylysine residues is unusually specific to collagen and collagen-like domains. Hydroxylysines generated by lysyl hydroxylases can be galactosylated by collagen galactosyltransferases COLGALT1 and COLGALT2 and, at selected sites, further glucosylated by lysyl hydroxylase 3/PLOD3. Recent structural work has begun to resolve how these enzymes recognise procollagen and coordinate sequential lysine processing. Functional studies outside the heart further indicate that altered collagen glycosylation can change secretion, fibril architecture and matrix stability. In contrast, direct causal evidence in myocardial fibrosis remains limited. This gap is important because pressure overload, ischaemia, cardiomyopathy and congenital heart disease all induce fibroblast activation and extensive collagen remodelling, but current antifibrotic strategies rarely target collagen maturation itself. In this review, we integrate current knowledge of collagen hydroxylysine glycosylation with cardiac fibroblast biology and myocardial extracellular matrix remodelling. We discuss the PLOD–COLGALT–LH3 enzymatic machinery, the potential consequences of glycosylation for collagen folding, secretion, fibrillogenesis, cross-linking and receptor signalling, and the evidence linking these processes to fibrotic disease. We then consider therapeutic strategies based on enzyme modulation, disruption of enzyme–substrate interactions, fibroblast-selective delivery and glycopeptide biomarkers. We argue that collagen glycosylation is best viewed not as an isolated biochemical decoration but as a candidate control point connecting intracellular collagen processing with extracellular matrix persistence. Establishing this concept in the heart will require site-resolved glycoproteomics, cell-specific genetic models and validation in human myocardial tissue.