Fig. 1

The mechanism of cuproplasia in HCC. The cuproplasia is defined as the copper-dependent cell growth and proliferation, containing both neoplasia and hyperplasia. Copper is translated by the SLC31A1, and ATP7B and forms into the labile pool. (1) Copper could decrease the level of G6PDH and GRD, leading to the production of ROS and decreased antioxidant function, thus increasing the risk of genetic mutations in hepatocytes. Besides, through the BRAF-RAS-RAF-MEK-ERK and PI3K-PDK1-PKB signaling pathways, the risk of genetic mutations is increasing collectively in order to contribute to neoplasia. (2) Copper could promote hyperplasia through the mitochondrial pathways and non-mitochondrial pathways. Copper is the cofactor of various respiratory enzymes, the elevated copper could increase the number and the function of the respiratory enzymes in mitochondria such as the CCS, SOD1, COX, and ATOX1, thus the mitochondrial respiration is enhanced. Besides, copper could inhibit the PDE, which could degrade the cAMP. Thus, more triglycerides are transformed into glycerol and fatty acids through cAMP pathway, increasing the lipolysis in HCC, and consequently promoting tumor proliferation. (3) In addition, copper alleviates the ULK1 and ULK2 pathways to enhance autophagic flux, providing more copper-dependent targets for tumor proliferation by controlling protein quality. (4) Furthermore, copper is involved in the COMMD family and LOX family through HIF1α/VEGF/NF-κB pathway and ATOX–ATP7A–LOX pathways, then the angiogenesis is promoted. All of those above lead to hyperplasia. ATOX1 antioxidant protein 1, cAMP 3',5'-cyclic AMP, cdc25 cell division cyclin25, CCS copper chaperone for superoxide dismutase, COMMD copper metabolism MURR1 domain, COX cytochrome c oxidase, eNOS endothelial nitric oxide synthase, G6PDH glucose 6-phosphate dehydrogenase, LOX lysyl oxidase, MEK1/2 mitogen-activated protein kinase kinase 1/2, HIF-1α hypoxia-inducible factor-1α, mTOR mammalian target of rapamycin, Nf-kB Nuclear factor kappa-B, NO nitric oxide, p53 transformation-related protein 53, PDE phosphodiesterase, PDK1 3-Phosphoinositide-dependent protein kinase 1, PDGF platelet-derived growth factor, PI3K phosphatidylinositol 3-kinase, PKB protein kinase B, ROS reactive oxygen species, SCO1 synthesis of cytochrome c oxidase 1, SOD recombinant superoxide dismutase, STEAPs Six-transmembrane epithelial antigen of the prostate, ULK Unc-51 Like Autophagy Activating Kinase, VEGF vascular endothelial growth factor