The Role of Renalase in Cardiovascular Disease: A Comprehensive Review of Its Molecular Biology, Genetic Associations, and Clinical Significance

Renalase, a flavin adenine dinucleotide (FAD)-dependent enzyme/hormone, has emerged as a molecule of significant interest in cardiovascular medicine since its discovery nearly two decades ago. Initially proposed as a catecholamine-degrading enzyme crucial for blood pressure regulation, its functional repertoire has expanded to include potential α-NAD(P)H oxidase/anomerase activity and roles as a signalling cytokine. This review synthesises the current understanding of renalase, encompassing its fundamental biology, intricate gene regulation by transcriptional factors, microRNAs, and physiological stimuli, and its implications in cardiovascular health and disease. A central focus is the critical appraisal of circulating renalase as a clinical biomarker. We critically evaluate findings from preclinical animal and cellular models related to atherosclerosis, heart failure, and blood pressure control. Furthermore, this review examines the extensive literature on RNLS gene polymorphisms and their associations with human cardiovascular phenotypes, alongside the complex and often context-dependent data regarding circulating renalase levels as a potential clinical biomarker in conditions such as hypertension, coronary artery disease, atrial fibrillation, and heart failure. While renalase shows context-specific promise, its multifaceted biology and the current methodological disparities limit its immediate clinical application. This review concludes by outlining a clear path forward, emphasising the need for standardised research and mechanistic studies to unlock the true diagnostic and therapeutic potential of renalase in CVD. © 2025 by the authors.