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  • Review Article
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Cholesterol crystals in the pathogenesis of atherosclerosis

Nature Reviews Cardiology volume 22, pages 315–332 (2025)Cite this article

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Abstract

The presence of cholesterol crystals (CCs) in tissues was first described more than 100 years ago. CCs have a pathogenic role in various cardiovascular diseases, including myocardial infarction, aortic aneurysm and, most prominently, atherosclerosis. Although the underlying mechanisms and signalling pathways involved in CC formation are incompletely understood, numerous studies have highlighted the existence of CCs at various stages of atheroma progression. In this Review, we summarize the mechanisms underlying CC formation and the role of CCs in cardiovascular disease. In particular, we explore the established links between lipid metabolism across various cell types and the formation of CCs, with a focus on CC occurrence in the vasculature. We also discuss CC-induced inflammation as one of the pathogenic features of CCs in the atheroma. Finally, we summarize the therapeutic strategies aimed at reducing CC-mediated atherosclerotic burden, including approaches to inhibit CC formation in the vasculature or to mitigate the inflammatory response triggered by CCs. Addressing CC formation might emerge as a crucial component in our broader efforts to combat cardiovascular disease.

Key points

  • The presence of cholesterol crystals (CCs) in advanced atherosclerotic plaques was documented over a century ago and is associated with the accumulation of cholesterol from lipid-laden macrophages that die in the core of the atheroma.

  • CCs are produced by endothelial cells after only a short exposure to hyperlipidaemic conditions and are secreted to the basolateral side of the endothelium, resulting in the formation of a subendothelial space.

  • Although incompletely understood, the formation of CCs probably involves pathways that regulate lipid uptake, intracellular lysosome-mediated lipid metabolism, reverse cholesterol transport and autophagy.

  • CCs can be taken up by pattern recognition receptors on various cell types, including macrophages, smooth muscle cells and endothelial cells, and cause various inflammatory responses, including NLRP3 inflammasome activation.

  • The in vivo imaging and detection of CCs need to be improved to identify vulnerable atherosclerotic plaques that are associated with an increased risk of future cardiovascular events.

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Fig. 1: Pathways activated by cholesterol crystals in various cell types.
Fig. 2: Pathways involved in cholesterol crystal formation.
Fig. 3: Fundamental processes implicated in atherogenesis.
Fig. 4: Cholesterol crystal uptake and formation.
Fig. 5: Detection of cholesterol crystals across various stages of atherogenesis in a murine model of atherosclerosis.

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Authors and Affiliations

  1. Social Determinants of Obesity and Cardiovascular Risk Laboratory, NIH, NHLBI, Bethesda, MD, USA

    Yvonne Baumer

  2. Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    Jason Irei & William A. Boisvert

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  1. Yvonne Baumer
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  2. Jason Irei
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  3. William A. Boisvert
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The authors contributed substantially to all aspects of the article.

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Correspondence to William A. Boisvert.

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Baumer, Y., Irei, J. & Boisvert, W.A. Cholesterol crystals in the pathogenesis of atherosclerosis. Nat Rev Cardiol 22, 315–332 (2025). https://doi.org/10.1038/s41569-024-01100-3

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