Plasmalogen remodeling modulates macrophage response to cytotoxic oxysterols and atherosclerotic plaque vulnerability.

Essential fatty acid metabolism in myeloid cells plays a critical but underexplored role in immune function. Here, we demonstrate that simultaneous inactivation of two key enzymes involved in macrophage polyunsaturated fatty acid (PUFA) metabolism-ELOVL5, which elongates long-chain PUFAs, and LPCAT3, which incorporates them into phospholipids-disrupts membrane organization by promoting the formation of cholesterol-enriched domains. This increases macrophage sensitivity to cytotoxic oxysterols and leads to more vulnerable atherosclerotic plaques with enlarged necrotic cores in a mouse model of atherosclerosis. In humans, analysis of 187 carotid plaques reveals a positive correlation between LPCAT3/ELOVL5-generated phospholipids-including arachidonate (C20:4 n-6)-containing ether lipids-and more stable plaque profiles. Additionally, Mendelian randomization analysis supports a causal relationship between LPCAT3 expression and reduced risk of ischemic stroke. Our findings uncover a regulatory circuit essential for PUFA-containing phospholipid generation in macrophages, positioning PUFA-containing ether lipids as promising biomarkers and therapeutic targets.