From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases.

backgroundAutoimmune diseases (AIDs) are characterized by disrupted immune tolerance, chronic inflammation, and organ-specific tissue injury. Their pathogenesis involves the interplay between genetic susceptibility and environmental factors. Although current biological agents and glucocorticoid therapies have improved clinical outcomes, long-term remission rates remain limited, with persistent risks including infection, organ toxicity, and immunogenicity. Emerging evidence indicates that copper homeostasis imbalance, mitochondrial dysfunction, redox stress, and immunometabolic remodeling coexist in multiple systemic and organ-specific AIDs. Cuproptosis, a newly identified form of regulated cell death, provides a potential mechanistic framework to understand the convergence of these pathological processes. However, direct in vivo evidence of canonical cuproptosis in autoimmune lesions remains scarce, and most relevant studies rely on transcriptomic associations, public dataset mining, or model-dependent experiments. There is an urgent need to clarify conceptual boundaries and the hierarchy of evidence.

objectivesThis review aims to systematically distinguish the conceptual differences among copper dysregulation, copper-associated mitochondrial/redox stress, cuproptosis-related vulnerability, and canonical cuproptosis. It seeks to summarize the hierarchical levels and limitations of existing evidence, evaluate the translational potential of copper-modulating strategies in AIDs, and provide references for future research directions and clinical translation.

results1. A hierarchical evidence grading system for cuproptosis was established, categorizing existing evidence into six levels: bioinformatic inference (e.g., transcriptomic differential expression, immune infiltration correlation), disease-associated phenotypic evidence, functional perturbation evidence, rescue-based evidence, direct biochemical validation, and in vivo disease validation. It was clarified that canonical cuproptosis can only be confirmed when copper dependence, involvement of the Ferredoxin 1 (FDX1)-lipoylation axis, aggregation of lipoylated proteins, destabilization of Fe-S clusters, and functional rescue are demonstrated. 2. The characteristics of copper metabolism disorders and cuproptosis related molecular remodeling in systemic AIDs (e.g., systemic lupus erythematosus, rheumatoid arthritis) and organ-specific AIDs (e.g., inflammatory bowel disease, ankylosing spondylitis) were summarized. Findings mostly reflected copper-associated metabolic stress or susceptibility markers rather than definitive functional activation. 3. The immunometabolic regulatory roles of cuproptosis in immune cells-including macrophages, dendritic cells, and T cells-were analyzed, highlighting that their effects are cell-type and context dependent. 4. The limitations of copper-modulating strategies, such as copper chelators and copper ionophores, were evaluated, emphasizing that these currently represent hypothesis-generating approaches. Clinical application requires consideration of toxicity, targeting specificity, pharmacokinetics, and disease-context dependence.

conclusionsCurrent research on cuproptosis in AIDs is largely correlative, bioinformatic, or model dependent, and is insufficient to confirm canonical cuproptosis as a primary pathogenic mechanism in AIDs. Cuproptosis should be regarded as a conditional and hypothesis-generating framework. Future studies should adopt a rigorous evidence hierarchy, optimize diseaserelevant model selection, and validate its pathophysiological significance through direct biochemical assays. The clinical translation of copper-targeted therapeutic strategies still requires substantial foundational and clinical research support.