Mechanisms modulating foam cell formation in the arterial intima: exploring new therapeutic opportunities in atherosclerosis

This review overturns a textbook assumption: that the foam cells choking an atherosclerotic plaque are mostly macrophages. Lineage-tracing studies say otherwise — more than half come from the artery’s own smooth-muscle cells.

The mechanism is a kind of cellular identity crisis. Loaded with lipid, smooth-muscle cells reprogram themselves — shedding their contractile markers and switching on macrophage-like genes (driven by the transcription factor KLF4) — to become foam cells that are worse at clearing cholesterol than true macrophages. The review also spotlights two upstream levers: an individual’s susceptibility to LDL aggregation (clumped LDL, not native LDL, drives uptake) and the receptor LRP1 that smuggles aggregated LDL into these cells.

The practical takeaway is a wider therapeutic map than “lower LDL-C”: targets like KLF4, LRP1, LDL-aggregation propensity (influenced by dietary fats), and reverse cholesterol transport (e.g., LCAT therapy in early trials). The resistance is an industry and clinical culture anchored to established LDL-lowering.

We rate the evidence solid for a mechanistic review: a comprehensive synthesis of lineage-tracing and single-cell data, though heavily reliant on mouse models and early-stage therapeutics. Its clinical significance is moderate — a genuine paradigm shift in plaque biology that could eventually guide new drugs, but whose clinical payoff is mostly still ahead.