Cuproptosis in chemically induced neurotoxicity: current evidence and a testable framework for psychostimulant-induced neurotoxicity

Cuproptosis is a copper-dependent form of regulated cell death characterized by disruption of lipoylated mitochondrial proteins, iron-sulfur cluster instability, and proteotoxic stress. This review examines whether this pathway contributes to chemically induced neurotoxicity and to psychostimulant-associated neuronal injury. Recent experimental studies have expanded the neurotoxic contexts in which copper-dependent injury has been investigated, including environmental nanomaterials, toxic metals, copper overload, and pharmacological agents. Across these models, the strongest evidence combines altered copper homeostasis with pathway-specific molecular changes and functional intervention, although complete demonstration of canonical cuproptosis remains inconsistent. In psychostimulant models, the evidence is substantially less developed. Methamphetamine has recently been associated with alterations in ATP7A/B, FDX1, and lipoylated DLAT, whereas cocaine and synthetic cathinones remain supported mainly by mitochondrial, redox, and proteostatic abnormalities. None of these psychostimulant models has yet established copper-dependent neuronal death through the complete canonical pathway. The current literature therefore supports cuproptosis as an emerging mechanism in selected forms of chemically induced neurotoxicity, while its role in psychostimulant injury remains a testable but unconfirmed hypothesis.