Abstract
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, with macrophage dysfunction playing a central role in its pathogenesis. Ubiquitination, a critical post-translational modification, regulates diverse macrophage functions, including lipoprotein metabolism, inflammation, oxidative stress, mitophagy, autophagy, efferocytosis, and programmed cell death (pyroptosis, necroptosis, ferroptosis, and apoptosis). This review highlights the regulatory roles of ubiquitination in macrophage-driven CVD progression, focusing on its effects on cholesterol metabolism, inflammation, activation, polarization, and the survival of macrophages. Targeting ubiquitination pathways has therapeutic potential by enhancing macrophage autophagy, reducing inflammation, and improving plaque stability. However, challenges, such as off-target effects, ubiquitination crosstalk, and macrophage heterogeneity, must be addressed. By integrating advances in ubiquitination biology, therapeutic strategies can be developed to mitigate CVD and other macrophage-driven inflammatory diseases. This review underscores the potential of ubiquitination-targeting therapies for mitigating CVD and highlights the key areas for further investigation.