Background <p>Age-related macular degeneration (AMD) is a neurodegenerative disease associated with severe visual impairment in the elders. Despite recent studies and advances, the pathophysiology underlying the development of AMD is still not fully understood, and current therapies remain limited. Programmed cell death (PCD) has been implicated in neurodegenerative diseases. Therefore, the aim of this study is to investigate and identify key types of PCD and PCD-related genes involved in the pathogenesis of age-related macular degeneration (AMD).</p> Methods <p>This study employs transcriptomic analyses and animal experiments. For bulk tissue transcriptomic analysis, the enrichment scores of PCD forms in AMD samples were calculated using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Single-cell transcriptomic analysis was conducted to examine the expression of PCD-related genes across different cell types. A mouse model was used to evaluate the therapeutic effects of a copper chelator on AMD.</p> Results <p>Enrichment analysis indicated that cuproptosis was the most enriched type of PCD process in both AMD-affected macular and retinal pigment epithelium (RPE) samples. In addition, cuproptosis was associated with the progression of AMD. Single-cell transcriptomic analysis revealed that cuproptosis was highly activated in varies retinal cells from AMD samples when compared to normal ones. Pathway enrichment analysis showed that cuproptosis was associated with angiogenesis, inflammation, and cellular senescence in AMD. Furthermore, the copper chelator demonstrated a protective effect on retinal function in the AMD mouse model.</p> Conclusions <p>Our findings identified an important role of cuproptosis in the pathophysiology of AMD and suggested the potential of cuproptosis as a therapeutic target for AMD.</p>