Cuproptosis and copper metabolism regulate hepatocellular carcinoma progression and therapeutic response to sorafenib

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, and systemic therapy with sorafenib is limited by primary and acquired resistance. Copper is now recognized both as a growth-promoting cofactor in HCC and as the trigger of cuproptosis, a copper-dependent form of regulated cell death executed through ferredoxin-1 (FDX1)-mediated reduction of Cu²⁺, aggregation of lipoylated tricarboxylic acid (TCA) cycle proteins such as dihydrolipoamide S-acetyltransferase (DLAT), loss of Fe-S cluster proteins and proteotoxic mitochondrial stress. This review is deliberately restricted to a single mechanistic axis - copper handling, cuproptosis competence and sorafenib response in HCC - and grades the evidence supporting it. We distinguish direct experimental demonstrations of cuproptosis from copper overload, oxidative stress and mitochondrial injury, which are frequently but incorrectly treated as equivalent, and we apply the same standard to the noncoding RNA and immune literature, in which most cuproptosis-related lncRNA and miRNA signatures remain computationally derived and lack mechanistic proof or external validation. Current data indicate that sorafenib can create an intracellular environment permissive for cuproptosis, mainly through glutathione depletion and altered copper-transporter expression; a direct, sorafenib-specific action on the cuproptosis machinery, including the proposed stabilization of FDX1, is plausible but not yet established. We further summarize the emerging determinants of cuproptosis resistance and the translational barriers - systemic and hepatic copper toxicity, cirrhosis-related vulnerability, tumor heterogeneity, unfavorable pharmacokinetics of copper ionophores and chelators, and the absence of validated predictive biomarkers - that must be addressed before cuproptosis-directed strategies can reasonably be tested in patients with HCC.