Targeting cuproptosis in disease treatment: From molecular mechanisms to therapeutic interventions

Cuproptosis, a form of regulated cell death, involves the direct binding of copper ions to lipoylated proteins in the tricarboxylic acid (TCA) cycle. This binding induces the aggregation of lipoylated proteins and the loss of iron-sulfur cluster proteins, ultimately leading to proteotoxic stress and cell death. Notably, cuproptosis is highly dependent on mitochondrial respiration, particularly the integrity of the TCA cycle. Studies have shown that various diseases are associated with elevated local copper levels and/or systemic copper dysregulation. Consequently, modulating local or systemic copper metabolism to develop therapeutic strategies has emerged as a pivotal direction in current medical research. This review focuses on the complex regulatory mechanisms of copper metabolism and the molecular basis of cuproptosis, as well as the association between cuproptosis and the progression of various diseases. We systematically summarize recent advances in cuproptosis research across multiple fields, including cancer, neurodegenerative diseases, and bacterial infections, covering the design principles and mechanisms of related therapeutic strategies. Finally, we discuss the challenges and future directions in targeting cuproptosis for disease treatment. We hope this review will serve as a valuable reference for researchers in this rapidly evolving field. • A systematic elucidation of the cuproptosis mechanism and its intricate interplay with copper metabolism. • A comprehensive exploration of its dual role across major diseases, from cancer and infections to neurodegenerative and bone disorders. • A critical analysis of current challenges and forward-looking strategies that integrate nanotechnology, immunotherapy, and metabolic modulation.