Iron metabolism is strongly connected to oxidative stress, the excessive production of reactive oxygen species and other oxidative molecules that outpaces the ability of cells to avoid, resist, or repair the consequent damage. It can lead to a form of programmed cell death called ferroptosis. Here, researchers describe how iron metabolism and ferroptosis are seen to contribute to the development of atherosclerosis. This isn't a very well developed area of research into cardiovascular disease, in that while one can paint an interesting mechanistic picture at the high level, much of the detail remains to be filled in, and robust forms of therapy based on manipulation of iron metabolism or ferroptosis have yet to emerge.
Disturbances in iron homeostasis have a bidirectional impact on the development of atherosclerosis. The classic "iron hypothesis" states that systemic iron overload increases the risk of cardiovascular diseases (CVDs), while controlling iron deficiency can protect blood vessels. Histopathological studies have confirmed that atherosclerotic plaques have a higher iron deposition compared to healthy blood vessels, and this phenomenon can be observed from the early stages of atherosclerosis. Macrophages recycle iron from senescent red blood cells, and intra-plaque hemorrhage exacerbates the phagocytosis of red blood cells, which is considered a key mechanism for iron deposition.
An increase in intracellular iron concentration enhances the uptake of oxidized low-density lipoprotein (ox-LDL), hinders cholesterol efflux, and accelerates the formation of foam cells in the plaque environment. This process leads to a decrease in GPX4 expression, an excessive production of reactive oxygen species (ROS), and an exacerbation of lipid peroxidation - all three together exacerbate intracellular oxidative stress, directly aggravating endothelial dysfunction and ultimately increasing plaque instability.
Despite the promising therapeutic potential of targeting ferroptosis discussed throughout this manuscript, several important limitations must be acknowledged. First, the disease specificity of ferroptosis-driven pathology remains incompletely defined; not all conditions involving cell death or oxidative stress may benefit from ferroptosis inhibition, and the contribution of ferroptosis varies substantially across different diseases and even across stages of the same disease. Second, the optimal timing of intervention is challenging to determine, as ferroptosis may play divergent roles in early versus late disease phases, and premature or delayed intervention could be ineffective or even detrimental. Third, systemic modulation of iron metabolism carries risks of off-target effects on other organs, including potential hepatotoxicity, cardiotoxicity, and disruption of normal iron homeostasis in tissues with high iron turnover. Fourth, while natural compounds are often proposed as ferroptosis modulators, they have pharmacological limitations such as poor solubility, low bioavailability, off-target bioactivity, and unknown long-term safety profiles.
Link: https://doi.org/10.1016/j.redox.2026.104330
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