Macrophage Gpx4 deficiency aggravates foam cell formation by regulating the expression of scavenger receptors, ABCA1, and ABCG1

Abstract Macrophage‐derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low‐density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre‐loxP system, we generated myeloid cell‐specific Gpx4 knockout ( Gpx4 myel‐KO ) mice. Bone marrow‐derived macrophages (BMDMs) were isolated from WT and Gpx4 myel‐KO mice and incubated with modified low‐density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX‐1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage‐derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis‐related diseases.