Lysophosphatidylcholine and lysophosphatidic acid as key messengers in atherosclerosis: from a lipid-inflammation vicious cycle to therapeutic translation

The residual risk of atherosclerosis (AS) extends beyond low-density lipoprotein cholesterol (LDL-C) and involves a complex interplay between lipid metabolism and inflammation. Among lysophospholipids (LPLs), lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), the two most abundant and bioactive LPL species in AS plaques, serve as central hubs in this interaction. Hyperlipidemia provides the substrate for LDL oxidation; the resulting oxidized LDL is hydrolyzed by lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) to generate LPC, which is further converted by autotaxin to the more potent LPA. These LPLs activate specific G protein-coupled receptors (GPCRs) on endothelial cells, macrophages, and vascular smooth muscle cells, thereby triggering inflammatory signaling, impairing reverse cholesterol transport, and promoting macrophage pyroptosis. Spatial metabolomics has identified LPC (18:0) and LPA (18:1) as subspecies enriched in macrophage-rich regions of vulnerable plaques, providing direct in-situ evidence for their pathogenic roles. This review systematically examines the biosynthesis, receptor-mediated signaling, and pathological effects of LPC and LPA in AS, with an emphasis on the LPC-LPA axis as a self-reinforcing driver of plaque progression and destabilization. We further critically evaluate translational advances, including failed clinical trials of Lp-PLA 2 and autotaxin inhibitors, and discuss emerging strategies such as multi-node combination therapy and subtype-specific precision targeting of LPLs. By integrating mechanistic insights with spatial metabolomics and therapeutic perspectives, this review aims to inform future strategies to overcome the residual risk of AS.