Ubiquitination regulation in coronary microcirculation dysfunction: focus on the endothelial cells

Basic and clinical research on coronary microvascular disease (CMD) has spanned half a century. As a pathogenesis independent of epicardial coronary stenosis, CMD has become a major hotspot in cardiovascular medicine. Ubiquitination, a vital post-translational modification in eukaryotic cells, precisely regulates target proteins via the E1-E2-E3 enzymatic cascade and plays a critical role in cardiovascular homeostasis and pathophysiology. Recent evidence indicates that the ubiquitin-proteasome system (UPS) is deeply involved in the development of CMD by modulating nitric oxide production, barrier function, and inflammatory signaling in coronary microvascular endothelial cells. This review summarizes recent advances in ubiquitination, elaborates its molecular mechanisms in regulating coronary microcirculation, and dissects its pathogenic roles in diabetes, hypertension, and myocardial ischemia/reperfusion injury (MIRI).We further discuss potential therapeutic strategies and translational challenges of targeting the ubiquitination pathway for CMD, including proteasome inhibitors, E3 ligase modulators, deubiquitinase agonists, and PROTACs, aiming to provide new insights for future research.