From Endoplasmic Reticulum Homeostasis to Cardiac Protection: The Role of UFMylation in Cardiovascular Diseases

The development and progression of cardiovascular diseases (CVDs) are closely linked to an imbalance in endoplasmic reticulum homeostasis. UFMylation, a recently identified ubiquitin-like post-translational modification, plays a crucial role in maintaining cellular homeostasis by regulating substrate protein functions through a unique enzymatic cascade. Accumulating evidence has demonstrated that UFMylation exerts complex regulatory effects on the pathogenesis of atherosclerosis, primarily by modulating endothelial function, macrophage foam cell formation, and inflammasome activation. Furthermore, UFMylation of the calcium-regulating protein SPCA1 disrupts calcium homeostasis in hypertrophic cardiomyopathy. Conversely, UFMylation also exhibits protective roles; for instance, it prevents pathological cardiac remodeling in heart failure by maintaining endoplasmic reticulum function via its E3 ligase, UFL1. Accordingly, this review systematically summarizes these multifaceted protective mechanisms of UFMylation in CVDs. We also explore potential therapeutic strategies targeting UFMylation, discussing its promise as a CVD biomarker and the opportunities and challenges in developing UFMylation agonists. In-depth research in this field is expected to provide novel theoretical foundations and precise intervention targets for the prevention and treatment of CVDs.