Review synthesizing mechanistic links between iron and copper dysregulation and regulated cell death (ferroptosis and cuproptosis), highlighting brain-penetrant chelators (e.g., SK4), radical-trapping agents (e.g., CuII(atsm)), and the 'iron trap' mechanism that connects copper deficiency to…

Provides actionable, translationally relevant targets and delivery strategies (LAT1-targeting, site-specific chelation, ferroxidase biomarkers, glutathione/ATP readouts) that could be prioritized for neuroprotective therapeutic development and repurposing in Parkinson's disease.

Dysregulation of iron and copper homeostasis is a pivotal driver of regulated cell death through two distinct yet interconnected modalities: ferroptosis and cuproptosis. This comprehensive review evaluates the therapeutic modulation of these metal-driven pathways within a dual paradigm: their deployment as a cytotoxic weapon in oncology and their inhibition for neuroprotection. We synthesize evidence ranging from small-molecule synergy to advanced nanomedicine, examining how the interplay between iron and copper governs cellular fate in resistant malignancies and neurodegenerative diseases such as Parkinson's disease and Multiple Sclerosis. In oncology, bimetallic nanoplatforms and CRISPR-Cas9 nano-ionophores exploit "iron addiction" and metabolic vulnerabilities to induce fatal lipid peroxidation and FDX1-mediated proteotoxic stress, often by circumventing efflux transporters like ATP7A/B. Conversely, neuroprotective strategies focus on site-specific chelation, utilizing brain-penetrant molecules like SK4 (targeting the LAT1 transporter) and radical trapping antioxidants like CuII(atsm). Importantly, we elucidate the "iron trap" mechanism, where copper deficiency inactivates multicopper ferroxidases-including ceruloplasmin and hephaestin-thereby triggering iron-dependent ferroptosis. Our analysis reveals a self-amplifying cycle of oxidative damage driven by metal-induced ATP depletion and glutathione exhaustion. By delineating the molecular machinery of iron and copper metabolism, this article provides a roadmap for leveraging regulated cell death to overcome apoptosis resistance in cancer and preserve neural integrity in chronic degeneration.