Cuproptosis: Biochemical Mechanisms, Therapeutic Potential, and Clinical Challenges

Cuproptosis is a novel form of regulated cell death, discovered in 2022, that occurs due to excessive copper accumulation in mitochondria. Unlike apoptosis, ferroptosis, pyroptosis, and necroptosis, cuproptosis depends on lipoylation of TCA cycle proteins, particularly DLAT, mediated by FDX1, and is accompanied by aggregation of lipoylated proteins and loss of Fe-S cluster proteins. This essay critically reviews the biochemical mechanisms of cuproptosis, its dual role in carcinogenesis (cuproplasia vs. cuproptosis), as well as its involvement in the pathogenesis of cardiovascular, neurodegenerative, metabolic, and musculoskeletal diseases. Therapeutic strategies are considered: copper ionophores (elesclomol, disulfiram), chelators (TTM, D-penicillamine), and nanotechnological delivery systems. Despite its substantial therapeutic potential, the clinical translation of cuproptosis-targeted strategies remains constrained by the lack of specific biomarkers, the complexity of selectivity control, and contradictory results of clinical trials. The need for biomarker-guided stratification of patients (e.g., by LDH level, FDX1 expression, ARID1A mutation status) and the development of tumor-specific nanosystems to minimize systemic toxicity are substantiated. The central thesis posits that cuproptosis is not merely a novel form of cell death, but a fundamental biochemical switch revealing the dual nature of copper; however, its clinical translation hinges on overcoming key limitations (Figure 1).