Ubiquitin E3 ligases in atherosclerosis: mechanisms of vascular cell plasticity and opportunities for targeted protein degradation

Atherosclerosis is a chronic inflammatory disease driven by coordinated dysfunction of endothelial cells, macrophages, and vascular smooth muscle cells (vSMCs). Increasing evidence identifies E3 ubiquitin ligases as central regulators of vascular homeostasis by controlling protein stability, signaling, and cellular plasticity through the ubiquitin–proteasome system. Rather than functioning as isolated regulators of individual substrates, E3 ligases integrate inflammatory, metabolic, oxidative, and mechanical cues to orchestrate the cell-state transitions that underlie plaque initiation, progression, and stability. In this Review, we highlight recent advances in the roles of E3 ubiquitin ligases across the major vascular cell types involved in atherosclerosis. In endothelial cells, E3 ligases regulate barrier integrity, inflammatory activation, endothelial-to-mesenchymal transition, and vascular cell crosstalk. In macrophages, they coordinate cholesterol homeostasis, inflammatory signaling, and efferocytosis, thereby influencing foam cell formation and plaque remodeling. In vSMCs, E3 ligases govern phenotypic plasticity, osteogenic differentiation, and extracellular matrix homeostasis, ultimately determining fibrous cap integrity and vascular calcification. These shared mechanisms identify ubiquitination as a systems-level regulator of vascular biology rather than a collection of cell type-specific pathways. We further discuss how these mechanistic insights are driving the development of targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders, as emerging therapeutic approaches for cardiovascular disease. Defining vascular ubiquitination networks and expanding the repertoire of druggable E3 ligases will be critical for translating ubiquitin biology into precision therapies that restore vascular homeostasis and improve outcomes in atherosclerotic cardiovascular disease.