Cuproptosis: A Potential Target for the Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by multi-organ involvement and broad immunological abnormalities, including persistent positive anti-nuclear antibodies. Different from many other autoimmune disorders, SLE is associated with significant disruption of copper homeostasis. Accumulating clinical evidence demonstrates elevated serum copper concentrations in SLE patients, which are closely associated with disease activity and inflammatory status. Despite advances in disease management, effective therapeutic options for SLE remain limited. Most SLE patients still require nonsteroidal anti-inflammatory drugs, immunosuppressants, and glucocorticoids, yet these treatments are frequently associated with adverse events and variable efficacy, particularly with long-term glucocorticoid use. For refractory SLE cases and patients experiencing chronic glucocorticoid-related toxicity, novel therapeutic strategies targeting cuproptosis are urgently required. Although biologic therapies have broadened available treatment options, their high cost and increased infection risk limit widespread clinical application. Its complex pathogenesis and pronounced clinical variability make personalized management strategies highly challenging. Identifying new molecular mechanisms and therapeutic targets, therefore, remains a major focus in SLE research. Recent studies have revealed a newly recognised form of programmed cell death, termed cuproptosis, within SLE-related pathological processes. Copper-mediated cuproptosis is driven by enhanced mitochondrial metabolism and excessive reactive oxygen species accumulation, processes that may promote immune-cell activation and inflammatory injury in SLE. Several key regulators are involved in this pathway, including ferredoxin 1 (FDX1); the lipoic-acid synthesis and protein lipoylation enzymes lipoic acid synthase (LIAS), lipoyltransferase 1 (LIPT1), and dihydrolipoamide dehydrogenase (DLD); pyruvate dehydrogenase complex (PDHC) subunits PDHA1 and PDHB, and dihydrolipoamide S-acetyltransferase (DLAT); as well as additional regulatory factors, including glutaminase (GLS), metal-regulatory transcription factor 1 (MTF1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). This review explores the relationship between cuproptosis and ten associated genes, their roles in dysregulated immune responses, and the emerging opportunities and challenges in developing therapeutic targets and clinical interventions.