Copper dyshomeostasis and cuproptosis in neurodegenerative diseases: metabolic and inflammatory therapeutic targets

Dysregulated copper metabolism has attracted increasing attention in neurodegenerative diseases, but its causal position within disease progression remains incompletely defined. Cuproptosis is a copper-dependent form of regulated cell death characterized by aggregation of lipoylated tricarboxylic acid (TCA)-cycle proteins and loss of iron–sulfur (Fe–S) cluster proteins, providing a mechanistically specific framework that is distinct from nonspecific copper-induced oxidative injury. In neurodegenerative settings, cuproptotic stress is most plausibly viewed as a context-dependent mitochondrial lesion whose expression depends on labile copper availability, mitochondrial respiratory dependence, protein lipoylation, and antioxidant reserve. It may increase ferroptotic and apoptotic susceptibility through shared liabilities in glutathione metabolism, Fe–S cluster integrity, and mitochondrial stress signaling. Current evidence further supports a layered response hierarchy in which Nrf2–ATF4 mediates early adaptation, NF-κB–p53 contributes to inflammatory and pro-death amplification, and HIF-1α–MTF1 modifies the vascular and metabolic context. Neuronal vulnerability is disease- and region-specific, whereas astrocytes, microglia, oligodendrocytes, and brain endothelial cells determine whether copper stress is buffered or propagated. We therefore frame copper-driven injury as a disease-stratified, multicellular process and discuss biomarker-guided approaches for distinguishing copper overload, maldistribution, impaired utilization, and downstream inflammatory amplification. Cuproptosis links copper overload to mitochondrial proteotoxic stress Fe-S loss and GSH depletion connect cuproptosis with ferroptosis Nrf2-ATF4 and NF-kB-p53 define adaptive and inflammatory modules Glial buffering may shape copper-driven neuronal vulnerability Biomarker-guided targeting may stratify copper-related neurodegeneration