USP18 Promotes Cholesterol Efflux and Mitigates Atherosclerosis by Deubiquitinating ABCG1

Deubiquitinating enzymes (DUBs) are integral regulators of protein stability. Among these, Ubiquitin-specific protease 18 (USP18) has emerged as a potential therapeutic target for heart failure. However, its precise role in atherosclerosis remains to be comprehensively understood. This study endeavours to examine the impact of USP18 on atherosclerosis and elucidate its corresponding molecular mechanisms. Our studies indicate an elevated expression of USP18 in human coronary atherosclerotic plaques. Notably, the knockdown of USP18 significantly exacerbated lipid accumulation in macrophages. This knockdown effect impaired cholesterol efflux and influenced the downregulation of ATP-binding cassette transporter G1 (ABCG1) expression, achieved by altering the ubiquitination level of ABCG1. Comprehensive mechanistic studies unveiled that USP18 directly affiliates with ABCG1, reducing its ubiquitination and consequently bolstering ABCG1 stability within macrophages. Furthermore, in vivo studies elucidated that the knockdown of USP18 notably elevated atherosclerotic lesions and diminished ABCG1 levels in the plaques of Apoe^-/- mice. In summary, our results suggested that USP18 plays a crucial role in managing the progression of atherosclerosis by strengthening the expression of ABCG1 protein through its deubiquitinating effect on ABCG1.