Cuproptosis and ferroptosis: signal pathways, diseases and therapeutic targets.

Regulated cell death is essential for tissue homeostasis, and its dysregulation contributes to numerous human diseases. Cuproptosis and ferroptosis are metal-dependent forms of regulated cell death distinguished by different biochemical triggers and pathological consequences. Cuproptosis arises from copper-mediated disruption and aggregation of lipoylated mitochondrial proteins, whereas ferroptosis is driven by iron-dependent phospholipid peroxidation. Despite these mechanistic differences, the two pathways intersect through mitochondrial metabolism, redox imbalance, iron-sulfur cluster biology, and organelle crosstalk. Lysosomes, mitochondria, and the endoplasmic reticulum act as critical regulatory hubs that influence cellular susceptibility to both death modalities. This review summarizes current understanding of the molecular mechanisms governing cuproptosis and ferroptosis. It examines the genetic, epigenetic, transcriptional, post-transcriptional, and protein-level networks that regulate these processes. Evidence linking cuproptosis and ferroptosis to cardiovascular, neurodegenerative, autoimmune, metabolic, oral, infectious, and neoplastic diseases is critically evaluated. Therapeutic approaches are discussed, including metal ionophores, chelators, small-molecule modulators, nanomedicine-based delivery systems, and rational combination strategies. Particular attention is given to the context-dependent consequences of activating or suppressing these pathways, and to the challenge of selectively targeting diseased tissues without disrupting systemic metal homeostasis. Successful clinical translation will require reliable biomarkers, mechanistically informed patient stratification, tissue-selective delivery, and a clearer understanding of interactions between metal metabolism, immune responses, and treatment resistance. The review further identifies unresolved questions concerning pathway specificity, temporal regulation, biomarker validation, and the clinical safety of systemic or prolonged therapeutic modulation. Integrating these concepts may enable more precise exploitation of cuproptosis and ferroptosis as therapeutic targets across diverse diseases.