Cuproptosis in stroke: Molecular mechanisms and therapeutic targeting of copper-mediated cell death

The recent identification of cuproptosis, a regulated cell death pathway dependent on copper, has reshaped our understanding of post-stroke neurodegeneration. This review comprehensively analyzes the dual role of copper dyshomeostasis in stroke pathophysiology, emphasizing its contributions to mitochondrial impairment, disrupted protein lipoylation, and dysregulated copper-iron crosstalk. We delineate three principal mechanisms through which copper aggravates neuronal damage: (1) copper overload disrupts Fe-S cluster assembly, leading to subsequent collapse of the TCA cycle; (2) FDX1-driven thiol-redox imbalance induces proteotoxic stress; and (3) spatiotemporal control of CTR1 expression determines regional neuronal susceptibility. The paradoxical behavior of copper-serving as both neuroprotectant and neurotoxin-underscores the necessity for precisely regulated copper homeostasis in therapeutic strategies. Promising therapeutic candidates include nanoparticle-based delivery systems designed to enhance blood-brain barrier penetration, computationally engineered high-affinity copper chelators, and biphasic regimens that combine acute-phase copper scavenging with subacute-phase metabolic recovery. Preclinical investigations targeting copper chaperones (ATP7A/B) or FDX1 inhibition have demonstrated neuroprotective efficacy. However, clinical translation confronts significant challenges, particularly the need to achieve cell-type-specific copper modulation while avoiding systemic copper deficiency. Looking forward, we advocate for an integrated research framework that pioneers the convergence of single-cell metallomics, dynamic copper imaging, and CRISPR-edited organoid models to unveil cell-type-specific vulnerabilities to copper dysregulation. The concurrent development of microenvironment-responsive nanotherapies and copper metabolism-based diagnostic biomarkers is poised to bridge the critical gap between fundamental discovery and clinical implementation. This synthesis not only deepens the mechanistic understanding of copper in stroke pathology but also charts a definitive translational roadmap for pioneering cuproptosis-targeted therapeutics.