Foam cells: tracing the diverse cellular origins and their linked signaling pathways

Foam cells play a crucial role in the formation and progression of atherosclerotic plaque. In addition to classical monocytes and vascular smooth muscle cells (VSMCs), foam cells can also originate from dendritic cells, endothelial cells, and stem cells. VSMCs account for over 75% of foam cells in murine models and approximately 50% in human plaques. Foam cell formation involves dysregulated cholesterol homeostasis, including impaired uptake via scavenger receptors like CD36, impaired efflux via ABCA1/ABCG1, and defective autophagy. Formation is also regulated by multiple signaling pathways, including inflammatory (TLR4-NF-κB and NLRP3 inflammasome), metabolic (PPARγ-LXRα and PI3K/Akt), and microenvironmental (Notch and Wnt) pathways. This review summarizes the cellular origins and regulatory mechanisms of foam cells, providing insights for targeted atherosclerosis therapies.