Lysophosphatidylcholine as a mechanistic and therapeutic nexus in atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide despite intensive lipid-lowering therapy. Residual cardiovascular risk persists even in patients achieving optimal lipoprotein-cholesterol (LDL-C) levels, indicating that additional lipid mediators contribute to disease progression. Lysophosphatidylcholine (LPC), a bioactive lysophospholipid generated from phosphatidylcholine by cytosolic or lipoprotein-associated phospholipase A₂ (PLA₂), has emerged as a critical mediator linking dyslipidemia, inflammation, and vascular injury. LPC is highly enriched in oxidized LDL (oxLDL), electronegative LDL (LDL(-)), and lipoprotein(a) [Lp(a)], all of which represent highly atherogenic lipoprotein subclasses. This review delineates the metabolic origins of LPC, its transport via LDL, VLDL, and albumin, and its accumulation within atherosclerotic plaques. LPC promotes endothelial dysfunction, monocyte recruitment, foam-cell formation, and platelet activation, collectively driving plaque development and instability. Elevated LPC levels are consistently observed in metabolic disorders such as type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH), both of which exacerbate ASCVD risk. Although statins, ezetimibe, and PCSK9 inhibitors effectively lower LDL-C, they do not directly target LPC or its downstream inflammatory pathways. Clinical trials of lipoprotein-associated PLA₂ inhibitors (e.g., Darapladib) failed to reduce cardiovascular events, underscoring the complexity of LPC-related signaling. Future therapeutic approaches may involve enhancing lysophospholipase A₁ activity or selectively inhibiting LPC production to restore vascular homeostasis. In aggregate, LPC represents a mechanistic bridge between lipid metabolism, vascular inflammation, and thrombosis, underscoring its potential as a biomarker and therapeutic target for residual ASCVD risk.