Integrative Multi-Omics Analysis Reveals Key Metabolic Regulators and Prognostic Biomarkers in Pediatric and Adult Thyroid Cancer.

Thyroid cancer, including papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC), exhibits distinct molecular characteristics in adult and pediatric populations. Understanding these differences is vital for identifying therapeutic targets and prognostic biomarkers. We performed an integrative multi-omics analysis combining proteomics, phosphoproteomics, metabolomics, and RNA sequencing data from adult and pediatric thyroid cancer cohorts. Differential expression analyses were conducted for all the multi-omics data with false discovery rate adjustments. Enzyme mapping of metabolites was performed using MetaBridge, while cross-omics integration revealed 46 key genes associated with reprogrammed energy metabolism. Clinical relevance was evaluated through survival analyses on cBioPortal and KM plotter platforms, and immunotherapy responses were assessed based on gene expression profiles. The 46 identified genes, primarily involved in mitochondrial energy metabolism and oxidative phosphorylation, were strongly associated with poor disease-free and overall survival in PTC and ATC patients. In ATC, a high tumor mutation burden correlated with worse outcomes, underscoring its prognostic value. Additionally, seven genes (AK2, SUCLG2, NDUFV2, GLUD1, HADHA, ALDH1A1, and NADSYN1) were linked to improved responses to anti-PD-1 immunotherapy, highlighting their potential as biomarkers for treatment stratification. Furthermore, functional studies reveal that AK2 plays a key role in thyroid cancer progression. This study offers critical insights into thyroid cancer biology and provides a foundation for targeted therapies and personalized immunotherapy strategies to improve patient outcomes.