USP22 enhances atherosclerotic plaque stability and macrophage efferocytosis by stabilizing PPARγ

Atherosclerosis is a chronic inflammatory condition that poses a significant threat to human health, with macrophages playing a central role in its development. Ubiquitin-specific peptidase 22 (USP22) has been implicated in regulating macrophage-mediated inflammation; however, its function within the atherosclerotic microenvironment remains poorly understood. In this study, we demonstrated that overexpression of USP22 in macrophages attenuates the progression of atherosclerosis in ApoE⁻/⁻ mice. In contrast, USP22 knockdown in vitro led to heightened inflammatory responses, increased foam cell formation, and impaired efferocytosis by macrophages. Mechanistically, USP22 interacts with peroxisome proliferator-activated receptor gamma (PPARγ), suppressing its ubiquitination and thereby enhancing its stability, which in turn promotes macrophage efferocytosis. Furthermore, intraperitoneal administration of the USP22 inhibitor, USP22i-S02, aggravated atherosclerotic lesions in ApoE⁻/⁻ mice. Collectively, these findings suggest that USP22 plays a protective role in atherosclerosis and may serve as a promising therapeutic target for disease intervention.