Cuproptosis: New Mechanisms Linking Endothelial Dysfunction to Neurodegenerative Diseases and Therapeutic Prospects

Cuproptosis is a copper-dependent form of regulated cell death driven by disrupted copper homeostasis and mitochondrial metabolic reprogramming. It is distinct from other cell death pathways and has been increasingly linked to vascular endothelial dysfunction and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This article comprehensively reviews the core molecular mechanisms of cuproptosis and its emerging roles in endothelial dysfunction and neurodegeneration, synthesizing recent findings from cellular, animal, and human studies. Cuproptosis exacerbates vascular pathology by impairing endothelial barrier function, inducing oxidative stress, and promoting inflammation and senescence. In the brain, it drives neurodegeneration both directly—via mitochondrial damage and neuronal loss—and indirectly by interacting with pathological proteins such as amyloid-beta and α-synuclein, creating a vicious cycle of copper dysregulation and protein aggregation. This review provides new insights into the pathophysiology of vascular endothelial dysfunction and neurodegenerative diseases by highlighting the pivotal role of cuproptosis. Understanding how cuproptosis links copper metabolism to cell death pathways opens avenues for identifying novel therapeutic targets. Interventions that restore copper homeostasis or block cuproptosis-specific molecular events may offer promising strategies for treating these devastating diseases.