USP22 enhances atherosclerotic plaque stability and macrophage efferocytosis by stabilizing PPARγ

Atherosclerosis is a chronic inflammatory disease that strongly threatens human health, and macrophages play a pivotal role in its pathogenesis. Ubiquitin-specific peptidase 22 (USP22) is involved in the regulation of macrophage inflammation. However, its role in the atherosclerotic microenvironment remains unclear. In this study, we found that USP22 overexpression in macrophages alleviated atherosclerosis progression in ApoE^-/- mice. In vitro, USP22 silencing enhanced macrophage inflammation and foam cell formation, and macrophage efferocytosis was significantly impaired. Mechanistically, USP22 bound to peroxisome proliferator-activated receptor γ (PPARγ) and inhibited its ubiquitination, thereby stabilizing PPARγ and promoting efferocytosis. In addition, intraperitoneal injection of the USP22 inhibitor USP22i-S02 exacerbated atherosclerosis in ApoE^-/- mice. In summary, these findings indicate that USP22 may be a potential therapeutic target for the treatment of atherosclerosis.