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Introduction
Copper is an essential micronutrient and is required for a wide range of physiological processes in all cell types in humans. Therefore, copper homeostasis is highly important and the accumulation of intracellular copper can lead to oxidative stress, resulting in perturbed cellular function. Recently, a new pattern of cell death, named copper-dependent death, has been reported and its mechanism was distinct from other mechanisms known to regulate cell death as it was demonstrated to occur through the direct binding of copper to lipid components of the tricarboxylic acid (TCA) cycle (1). The dihydrolipoamide dehydrogenase (DLD) gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family, and is a key regulator of the TCA cycle that has also been identified as a moonlighting protein based on its ability to regulate energy metabolism and the cell cycle (2). In the TCA cycle, DLD catalyzes the reduction of NAD+ to NADH in the second dehydration step (3). Previous studies have found that DLD is one of seven genes (FDX1, LIPT1, LIAS, DLD, DLAT, PDHA1, and PDHB) that are involved in copper-dependent death (1,4). Among these genes, FDX1 is a reductase known to reduce Cu2+ to its more toxic form, Cu+, and to be a direct target of elesclomol (4). LIPT1, LIAS, and DLD are components of the lipoic acid pathway, and DLAT, PDHA1, and PDHB are protein targets of lipoylation (1,4,5). Tumor cells depend on glutaminolysis fuelling to carry out the TCA cycle and essential biosynthetic processes supporting tumor growth, and DLD, a dehydrogenase found in several multi-enzyme complexes that regulate energy metabolism, plays an important role in the tumor biological process (2). It is therefore important to perform a pan-cancer expression analysis of copper-induced cell death-associated genes. This information can be used to assess their association with clinical prognosis and asses their underlying molecular functions mechanistically. A pan-cancer analysis of FDX1 was recently conducted, and it was demonstrated that FDX1 was significantly associated with immune-related pathways (6). The expression level of FDX1 was also demonstrated to be correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes (6).
To the best of our knowledge, there is currently no pan-cancer evidence based on clinical big data that demonstrated the relationship...