Ferroptosis in Cardiovascular Disease Mechanisms

Ferroptosis is an iron‐dependent form of regulated cell death distinguished by the accumulation of lipid hydroperoxides in cellular membranes. In cardiovascular tissues, dysregulation of iron handling, antioxidant defences and lipid metabolism converge to trigger ferroptotic injury in cardiomyocytes, vascular smooth muscle cells and endothelial cells. This process contributes to the pathogenesis of atherosclerosis, ischaemia–reperfusion injury, heart failure and drug-induced cardiomyopathy. Central to ferroptosis is the decline of glutathione peroxidase 4 (GPX4) activity and depletion of reduced glutathione, which allows unchecked lipid peroxidation. Concurrently, alterations in iron storage and release, often mediated by ferritinophagy, amplify reactive iron pools that catalyse free-radical formation. The resultant oxidative damage promotes vascular remodelling, myocardial dysfunction and inflammatory signalling. Targeting key nodes in the ferroptotic pathway offers promising therapeutic avenues to mitigate cardiovascular injury and improve clinical outcomes.

Research from Nature Portfolio

Recent studies have shown that pro-ferroptotic signalling drives vascular smooth muscle cell (VSMC) senescence and accelerates arterial ageing. In aged arteries and senescent VSMCs, activation of lipid peroxidation pathways leads to NAD+ depletion, enhanced secretome-mediated paracrine senescence and increased vessel stiffness. Pharmacological or genetic blockade of key ferroptotic initiators restores NAD+ levels, reduces ferritinophagy and ameliorates arterial remodelling in preclinical models. In a proof-of-concept analysis of human arteries, higher markers of pro-ferroptotic activity correlated with increased pulse-wave velocity, underscoring translational relevance for ageing-associated cardiovascular disease.

Ferroptosis in Cardiovascular Disease Mechanisms publication trend

The graph below shows the total number of articles in ferroptosis in cardiovascular disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: Regulated cell death driven by iron-catalysed lipid peroxidation.

Lipid peroxidation: Oxidative degradation of polyunsaturated lipids yielding toxic hydroperoxide species.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides and guards against ferroptosis.

Ferritinophagy: Autophagic degradation of ferritin that releases stored iron into the labile pool.

NAD+: A redox cofactor required for mitochondrial function and repair processes in senescent cells.

References

1. Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discovery (2021).
2. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nature Communications (2024).
3. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight (2020).
4. The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes. Advanced Science (2023).
5. Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice. Theranostics (2023).