Objective: Atherosclerosis is a disease characterized by abnormal lipid metabolism, and the formation of foam cells is considered an early event of atherosclerosis. Intracellular cholesterol efflux mediated by ABCA1 and ABCG1 helps to reduce lipid accumulation in foam cells. Related studies have shown that autophagy and mTOR are involved in cholesterol efflux, but the role of p62, an autophagy substrate protein, has not been evaluated. Methods: THP-1 derived macrophages were incubated with ox-LDL to establish a foam cell model and treated with different autophagy inducers. The effects of p62 on cholesterol efflux were investigated using overexpression vectors, gene silencing and western blotting. Results: This study showed a blockage of autophagy and decreased expression of ABCA1 and ABCGI under the stress of excess ox-LDL in a concentration-dependent manner in THP-1 cells. Furthermore, the activation of autophagy led to increased expression of ABCA1 and ABCG1, as well as their upstream transcription factor LXR alpha, thereby promoting cholesterol efflux from foam cells. We also demonstrated that accumulated p62 played an important role during autophagy blockage, which was achieved by activating mTOR and then inhibited the expression of LXR alpha and its downstream target proteins ABCA1 and ABCGI. Conclusion: In conclusion, our experiments demonstrated that a p62/mTOR/LXR alpha signaling pathway was involved in cholesterol efflux mediated by ABCA1 and ABCG1 when autophagy blockage occurred. Our study offers a rationale for the development of autophagy and p62 as a new target for the treatment of atherosclerosis. (C) 2019 Elsevier Inc. All rights reserved.