To explore the emerging role of copper-dependent cell death in the pathogenesis of Systemic Lupus Erythematosus (SLE), investigate its relationship with ten associated genes and dysregulated immune responses, and assess the opportunities and challenges for developing novel therapeutic targets and clinical interventions.

This review synthesizes recent findings on copper-dependent cell death, a newly recognized form of programmed cell death implicated in SLE. It examines the mechanistic links between copper metabolism, mitochondrial energy metabolism, and the accumulation of reactive oxygen species leading to cytotoxicity. The analysis integrates these mechanisms with the known hypoxic and glycolytic reprogramming in key immune cell populations—including dendritic cells, monocytes, neutrophils, T lymphocytes, and B lymphocytes—to elucidate their combined role in promoting SLE pathogenesis. The review specifically focuses on the involvement of ten associated genes in these interconnected pathways.

The analysis reveals that copper-dependent cell death is a significant pathological process in SLE. Copper can enhance mitochondrial metabolism and drive oxidative stress, contributing to immune cell dysfunction. This process is intertwined with the hypoxic and glycolytic environment within immune cells, which supports the aberrant survival and proliferation of autoreactive lymphocytes and innate immune cells, thereby fueling SLE pathogenesis. Ten specific genes have been identified as being potentially central to the dysregulation of copper homeostasis and its convergence with immune-metabolic pathways in SLE.

Copper-dependent cell death represents a novel and significant mechanism in SLE pathogenesis, closely linked to metabolic reprogramming and immune dysregulation. The identification of ten associated genes provides a promising avenue for future research. Targeting the pathways of copper-dependent cell death offers a potential new frontier for therapeutic intervention, though significant challenges remain in translating these findings into clinical applications for this complex and heterogeneous disease.