Ubiquitin-specific proteases in Atherosclerosis: Exploring novel therapeutic strategies beyond conventional...

Atherosclerosis (AS) is one of the primary causes of cardiovascular disease that is already a worldwide issue necessitating a novel therapeutic approach. Recent studies reflect the key functions of ubiquitin-specific proteases (USPs) in AS pathogenesis. The effects of these enzymes on ubiquitination and cell stability control cellular processes including protein degradation, lipid metabolism, inflammation, and cell signaling. Interestingly, USPs have dual and context-specific roles in AS progression. An example is that USP14 enhances AS through the activation of mTOR signaling in smooth muscle cells but suppresses NF-κB in endothelial cells. USP20 enhances hepatic lipogenesis but has the opposite effect on the inflammation of vessels by smooth muscle cells. On this basis, USP9X affects the foam cell formation and stability of the plaque through altering lipid uptake by the CD36. Small-molecule inhibitors, CRISPR-based gene editing, and nanotechnology-based delivery systems are a few of therapeutic USPs targeting approaches that have emerged as an area of interest. Nevertheless, there is a significant gap in existing knowledge about the tissue- and cell-specific roles of USPs because the identical enzyme can have both protective and atherogenic impacts on one cellular environment. The absence of approaches that would allow the accurate, tissue-specific modulation of USPs are a vital obstacle to clinical translation. This review highlights the urgency of accuracy-based medicine approaches that incorporate tissue-selective targeting, advanced delivery mechanisms, and molecular profiling to safely and efficiently apply USP-based therapeutic approaches in AS. Filling these gaps is crucial for advancing USP-targeted interventions beyond traditional AS therapies.