Deciphering the interplay between cuproptosis and mitochondrial energy metabolism in thyroid cancer: a multi-omics...

Thyroid cancer (THCA) exhibits substantial heterogeneity in clinical outcomes. The interaction between cuproptosis, a novel copper-dependent form of cell death, and mitochondrial energy metabolism, a key regulator of cellular bioenergetics, may influence tumor behavior, yet its role in THCA is not fully elucidated. We integrated transcriptomic data from The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA, n = 510; 457 with survival information) and Gene Expression Omnibus (GEO) cohorts (n = 101). Genes related to cuproptosis and mitochondrial energy metabolism (CMEMRGs) were systematically identified. Bioinformatic analyses included consensus clustering, immune cell deconvolution (CIBERSORT, ESTIMATE), prognostic model construction (LASSO Cox regression), and pathway enrichment (GSEA). We identified a landscape of 460 CMEMRGs in THCA. Unsupervised consensus clustering based on prognostic CMEMRGs revealed two molecular subtypes (Subtype A, n = 393; Subtype B, n = 117) with distinct survival outcomes (p < 0.001). Subtype B was associated with an immune-enriched microenvironment, characterized by differential infiltration of lymphocytes including CD8 + T cells and naïve B cells, and exhibited lower Tumor Immune Dysfunction and Exclusion (TIDE) scores, suggesting a potentially more favorable response to immunotherapy. A prognostic signature comprising 15 CMEMRGs was refined to a 3-gene model (APOE, PRR15, and C3) using LASSO regression. This simplified signature demonstrated predictive value for 4-, 5-, and 6-year overall survival (area under the curve [AUC] = 0.853, 0.789, and 0.789, respectively). Patients stratified into high-risk groups by this model exhibited elevated stromal and immune scores. The risk score showed a trend toward independent prognostic value in multivariate analysis, though further validation is needed. Gene Set Enrichment Analysis (GSEA) indicated an association with MAPK signaling pathways, and protein-protein interaction analysis suggested a direct link between APOE and C3. This integrative analysis indicates that the cuproptosis-mitochondrial energy metabolism axis could be implicated in THCA heterogeneity. The identified molecular subtypes and the 3-gene prognostic signature could provide supplementary insights for risk stratification and warrant further investigation into personalized therapeutic strategies.