Cuproptosis as the new kryptonite of cancer: a copper-dependent novel cell death mechanism with promising implications for the treatment of hepatocellular carcinoma

Abstract

Copper is an essential element for critical cellular functions such as mitochondrial respiration, cholesterol biosynthesis and immune response. Altered copper homeostasis has been associated with various disorders, including cancer. The copper overload is known to contribute to tumorigenesis, angiogenesis and metastasis, and recently it has been suggested that the elevated level of this element may also create vulnerability to a novel cell death mechanism, named cuproptosis. Excessive amount of copper in mitochondria binds to lipoylated enzymes of the TCA cycle and forms insoluble oligomers. The aggregation of these oligomers and subsequent iron-sulfur cluster protein loss results in proteotoxic stress and eventual cell death. Hepatocellular carcinoma is a common malignancy with a low survival rate, despite the available treatment options. The discovery of cuproptosis led many researchers to explore its potential use in hepatocellular cancer therapy due to the rich mitochondria content of hepatic cells. In this regard, a number of genomic studies were conducted to discover several cuproptosis-related genes and explored their association with prognosis, survival and immunotherapy response. This review brings together the available data on the relationship between cuproptosis and hepatocellular cancer for the first time, and highlights some of the potential biomarkers or target molecules that may be useful in the treatment.

Keywords: Cuproptosis; Hepatocellular carcinoma; Immunotherapy; Metastasis; lncRNAs.

Fig. 1

The mechanism of cuproptosis induced by elesclomol. Cu⁺² is transported into mitochondria by elesclomol and reduced to Cu⁺¹ by ferredoxin-1 (FDX1). Cu⁺¹ then binds to dihydrolipoyl transacetylases (DLAT) and forms oligomer complexes, leading to the inhibition of the TCA cycle and eventual cell death