A brief glimpse at cuproptosis in aortic aneurysm and the therapeutic prospects

Cuproptosis is a newly identified form of regulated cell death triggered by copper-induced mitochondrial stress. Recent studies suggest that it plays a key role in maintaining vascular homeostasis and contributes to the development of aortic aneurysm (AA). This review summarizes current findings linking cuproptosis to AA pathogenesis. Mechanistically, excess copper causes disregulation of lipoylated tricarboxylic acid cycle enzymes (such as DLAT , DLD , and PDHA1 ), disruption of iron-sulfur cluster proteins, and mitochondrial dysfunction. Bioinformatic analysis of both human and animal AA samples has revealed consistent dysregulation of cuproptosis-related genes (CRGs), including FDX1 , LIPT1 , CDKN2A , DLD , and PIM1 , which are associated with disease progression and immune cell infiltration. Single-cell RNA sequencing highlights monocytes and macrophages as key responders to cuproptosis within the AA microenvironment. In parallel, experimental studies show that CRGs can promote smooth muscle cell death, further contributing to vessel wall weakening. Emerging therapies that target cuproptosis, such as copper chelators and small molecules like metformin and ME-344-show potential in mitigating AA in preclinical models. However, important questions remain, including the cell-type-specific roles of CRGs, their time-dependent regulation during disease progression, and the clinical feasibility of targeting cuproptosis in AA management.