Fig. 3

Cuproptosis and its mechanism in HCC. The cuproptosis is closely related to mitochondrial respiration and the TCA cycle and is triggered by the elesclomol, which could translate elevated extracellular copper to intracellular matrix not only the cell membrane importer SLC31A1 and exporter ATP7B. Besides, elesclomol could enhance the FDX1 to reduce Cu²⁺ to become the more toxic Cu⁺. FDX1 is the key enzyme of cuproptosis, causing Fe-S protein imbalance thus leading to the Fe-S cluster, and promoting the lipoylation of DLAT. The Cu + binds to the lipoylated DLAT aggregation to participate in the formation of the PDH complex, which could affect the mitochondrial TCA cycle, leading to ATP depletion. Depletion of ATP will lead to intracellular inflammation through the AMPK pathway. In addition, the lipoylated DLAT aggregation and excess Cu.⁺ could induce proteotoxic stress through mitochondrial lipidated protein oligomerization. Eventually, these serious consequences lead to the cuproptosis. AMPK Adenosine 5'-monophosphate(AMP)-activated protein kinase, ATP Adenosine 5'-triphosphate, ATP7B Adenosine 5'-triphosphatase copper transporting beta, DLAT dihydrolipoamide S-acetyltransferase, ECT electron transport chain, FDX1 ferredoxin 1, LIAS lipoic acid synthetase, TCA tricarboxylic acid, PDH Pyruvate dehydrogenase, SLC31A1 solute carrier family 31 member 1