Copper metabolism and cuproptosis: broad perspectives in the treatment of hepatocellular carcinoma

Abstract

Copper is an essential trace element that plays a pivotal role in multiple biological processes, including energy production and angiogenesis. It is also a vital cofactor necessary for the maintenance of biological functions and has been implicated in cancer development. The recently identified form of cell death, cuproptosis, has a unique induction mechanism-accumulated copper ions directly bind to lipoylated proteins in the mitochondrial tricarboxylic acid (TCA) cycle, triggering toxic protein aggregation and cell death. This process can be specifically induced by oxidative stress and mitochondrial dysfunction, providing a novel direction for the development of anti-tumor strategies that target copper metabolism. In hepatocellular carcinoma (HCC), there is a significant correlation between disturbances in copper metabolism and abnormalities in the cuproptosis pathway. HCC cells maintain pro-carcinogenic copper levels through the upregulation of copper transporter proteins such as copper transporter 1 (CTR1). Conversely, the dysregulation of the expression of key genes involved in cuproptosis (ferredoxin 1, lipoic acid synthetase) may mediate treatment resistance. In this review, we focus on the mechanism by which cuproptosis influences the occurrence and development of HCC, evaluate its potential as a diagnostic biomarker, and examine therapeutic strategies targeting this form of cell death (nanocarrier-based delivery of copper ion carriers, CRISPR-mediated editing of copper-regulated genes). These strategies may provide a novel perspective for overcoming the current therapeutic limitations of HCC.

Keywords: copper; copper chelators; copper ionophores; cuproptosis; cuproptosis-related genes; hepatocellular carcinoma.

Figure 1

Overview of cellular copper metabolism. Extracellular Cu²⁺ is converted to Cu⁺ by STEAP and is then transported across the cell membrane by CTR1. Inside the cell, cytosolic Cu chaperones, such as CCS and SOD1, bind Cu⁺ and assist in transporting it to distinct subcellular compartments. In mitochondria, Cu⁺ connects with CcO, thereby participating in the respiratory chain and redox processes. In the mitochondrial intermembrane, COX17 binds Cu⁺ and transfers it to SCO1 or COX11, aiding the inclusion of Cu⁺ into cytochrome oxidase subunits. In the TGN, ATP7A and ATP7B transfer Cu⁺ from the cytosol to the TGN lumen, thereby activating Cu-dependent enzymes in the secretory pathway. In the nucleus, Cu⁺ binds to transcription factors and drives gene expression. STEAP, six-transmembrane epithelial antigen of the prostate; ATP7A/B, copper-transporting ATPase 7A/7B; CcO, cytochrome c oxidase; CCS, copper chaperone for superoxide dismutase; COX11, cytochrome c oxidase 11; CTR1, copper transporter 1; SCO1, synthesis of cytochrome c oxidase 1; SOD1, superoxide dismutase 1; TGN, trans-Golgi network.

Figure 2

Overview of cuproptosis. Extracellular Cu²⁺ enters the cytoplasm via the copper transporter protein CTR1 and is then reduced to Cu⁺ by FDX1. ATP7A/ATP7B mediate copper efflux to maintain homeostasis. Cu⁺ accumulation in mitochondria triggers the loss of Fe-S clusters (FDX2 is involved in regulation); LIAS is inactivated, blocking lipid acylation metabolism; and Cu⁺ binds to DLAT, inducing its abnormal oligomerization and aggregation, leading to cuproptosis.

Figure 3

The effect of copper on ferroptosis. The circulating apoprotein TF binds to the TFRC and facilitates the endocytosis of Fe³⁺. This is followed by the conversion of Fe³⁺ to Fe²⁺ in endosomes, which is mediated by STEAP3. OH is produced via the Fenton reaction, which, in turn, leads to lipid peroxidation and the phenomenon known as “ferroptosis”. Meanwhile, copper can facilitate the Fenton reaction, leading to the formation of PLOOH and, consequently, ferroptosis. Cu⁺ directly binds to the C107 and C148 cysteine residues of the GPX4 protein, inducing its aggregation. These aggregates are subsequently recognized by the autophagy receptor TAX1BP1 and degraded via the autophagy pathway, with ferroptosis occurring in response to autophagy. TF, transferrin; TFRC, transferrin receptor; STEAP3, six transmembrane epithelial antigen 3; OH, hydroxyl radicals; PLOOH, phospholipid hydroperoxides; GPX4, glutathione peroxidase 4; TAX1BP1, tax1-binding protein 1.