by Association of Basic Medical Sciences of FBIH

Credit: Association of Basic Medical Sciences of FBIH

Atherosclerosis (AS) is a chronic inflammatory disease characterized by the buildup of lipids and immune cells in arterial walls, increasing the risk of cardiovascular conditions. While multiple factors contribute to AS, recent research highlights the role of copper, an essential trace element, in disease progression.

Copper plays a crucial role in mitochondrial function, oxidative stress regulation, and vascular health. However, excess copper can become toxic, triggering oxidative damage and inflammation—two key drivers of AS. A newly identified form of regulated cell death, known as cuproptosis, may be a critical mechanism linking copper imbalance to vascular damage.

The research is published in the journal Biomolecules and Biomedicine.

Cuproptosis is a unique, copper-dependent form of cell death that differs from apoptosis and necrosis. It occurs when intracellular copper binds to proteins involved in the tricarboxylic acid (TCA) cycle, leading to protein aggregation, mitochondrial dysfunction, and ultimately, cell death. This discovery underscores the importance of copper homeostasis in maintaining vascular health.

Several mechanisms explain how cuproptosis may drive AS progression:

• Oxidative stress and mitochondrial dysfunction: Excess copper generates reactive oxygen species (ROS), leading to oxidative damage that weakens blood vessel integrity and promotes plaque instability.
• Inflammatory activation: Elevated copper levels activate inflammatory pathways, such as NF-κB signaling, increasing cytokine production and immune cell recruitment to arterial walls.
• Lipid metabolism disruption: Copper influences cholesterol metabolism, promoting LDL oxidation and foam cell formation, both of which accelerate plaque development.
• Endothelial and smooth muscle cell dysfunction: Excess copper impairs endothelial function, reduces nitric oxide (NO) availability, and promotes smooth muscle cell proliferation—factors that contribute to arterial narrowing.

Given these mechanisms, targeting cuproptosis could open new avenues for AS treatment and prevention.

Recent studies have identified key cuproptosis-related biomarkers that could aid in early AS detection and intervention:

• Ferredoxin 1 (FDX1): Regulates copper-induced cell death.
• Solute carrier family 31 member 1 (SLC31A1): Controls intracellular copper uptake.
• Glutaminase (GLS): Helps mitigate oxidative stress and protect against copper toxicity.

These biomarkers may serve as diagnostic tools, enabling earlier detection and targeted therapies for AS.

Several strategies are being explored to regulate copper levels and mitigate cuproptosis-related damage in AS:

• Copper chelation therapy: Compounds like tetrathiomolybdate (TTM) help lower copper levels and reduce vascular inflammation.
• Copper ionophores: These agents selectively transport copper into cells, though further research is needed to refine their safety and effectiveness.
• Small-molecule inhibitors of copper chaperones: Targeting proteins like ATOX1 may help regulate copper homeostasis without disrupting essential biological functions.
• Nanomedicine-based therapies: Advances in nanotechnology offer precision approaches, such as curcumin-based nanoparticles that chelate excess copper and reduce oxidative stress.

While cuproptosis represents a promising target for AS treatment, several challenges remain:

• Biomarker validation: More research is needed to confirm the clinical relevance of cuproptosis-related markers.
• Mechanistic understanding: The exact interactions between cuproptosis, oxidative stress, and lipid metabolism require further study.
• Therapeutic safety: Strategies targeting copper must maintain essential physiological functions to avoid unintended consequences.

By addressing these challenges, researchers aim to develop more effective, targeted treatments for AS, improving cardiovascular health and reducing disease burden.

More information: Jiankang Wang et al, The molecular mechanisms of cuproptosis and its relevance to atherosclerosis, Biomolecules and Biomedicine (2025). DOI: 10.17305/bb.2024.11826

Provided by Association of Basic Medical Sciences of FBIH

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