Abstract

Hepatocellular carcinoma (HCC) is a metabolically active malignancy. Cuproptosis, a copper-dependent programmed cell death pathway, has been found to be closely associated with tumor progression. Cells with strong oxidative phosphorylation (OXPHOS) capacity exhibit heightened susceptibility to cuproptosis. We demonstrate that the tumor suppressor ASPP2 regulates the key cuproptosis modulator FDX1 by promoting NR2F2 recruitment to the FDX1 promoter in HCC. ASPP2 promotes intracellular copper accumulation through lipoylated protein oligomerization, thereby inducing cuproptosis. Furthermore, ASPP2 facilitates mitochondrial OXPHOS via enhanced tricarboxylic acid (TCA) cycle activity, which sensitizes HCC cells to cuproptosis. In vitro and in vivo experiments confirmed that ASPP2 overexpression suppresses tumor growth and synergizes with copper ionophores. Clinical specimen analysis revealed ASPP2–FDX1 co-expression in 90 HCC cases. A prognostic model incorporating ASPP2 and cuproptosis-related genes demonstrates superior survival prediction in TCGA cohorts. These findings establish the ASPP2–FDX1–NR2F2 axis as a metabolic-cuproptosis link and propose a novel therapeutic strategy for HCC.