Copper and cuproptosis: From homeostasis to pathogenesis.

Copper is an essential trace element whose dyshomeostasis contributes to a wide range of human diseases. The recent discovery of cuproptosis, a copper-dependent form of regulated cell death distinct from previously recognized pathways, has reshaped current understanding of copper-associated pathology. Cuproptosis is triggered by excessive intracellular copper and is characterized by the aggregation of lipoylated proteins in the tricarboxylic acid (TCA) cycle and the loss of iron-sulfur cluster proteins, ultimately leading to mitochondrial proteotoxic stress. This review summarizes the mechanisms governing systemic, cellular, and mitochondrial copper homeostasis, highlights the biochemical basis of cuproptosis, and discusses its involvement in neurological, cardiovascular, immune-related, oral inflammatory diseases, and cancers. Particular attention is given to the unique metal-microbial-immune interactions underlying periodontitis and peri-implantitis. Finally, we outline emerging therapeutic strategies targeting copper imbalance and cuproptosis, including copper ionophores, chelators, and ligand-based approaches, offering new insights into the prevention and treatment of copper-associated diseases.