Dihydrolipoamide dehydrogenase promotes hepatocellular carcinoma progression and modulates cuproptosis-dependent cell death.

Hepatocellular carcinoma (HCC) is a major cause of cancer deaths with few treatment options. Cuproptosis, a copper-dependent cell death pathway, is a promising therapeutic target for HCC. In the present study, cuproptosis-related genes in HCC were identified from GeneCards, with dihydrolipoamide dehydrogenase (DLD) emerging as the top hub gene via STRING and Cytoscape analysis. DLD was markedly overexpressed in HCC tissues compared to normal liver tissues (P = 4.6 × 10⁻⁵) and was associated with advanced TNM stage, fibrosis, and reduced overall survival in both the TCGA (P = 0.039) and ICGC (P = 0.002) cohorts. Multivariate analysis identified DLD as an independent prognostic factor (HR = 2.533). GSEA indicated that elevated DLD expression was linked to enhanced glycolysis/gluconeogenesis, tricarboxylic acid cycle, and pyruvate dehydrogenase complex regulation pathways. In vitro, knockdown of DLD inhibited HCC cell proliferation and increased cell death. Importantly, depletion of DLD heightened susceptibility to cuproptosis, which was further augmented by elesclomol to intensify cell death, decrease FDX1 expression, and deplete ATP levels, but effects that were reversed by tetrathiomolybdate. In conclusion, DLD promotes HCC progression through regulating cuproptosis sensitivity, serving as both a prognostic biomarker and a potential therapeutic target for enhancing cuproptosis-based therapies in HCC.