Single-Cell and Mendelian Analyses Reveal Shared Mechanisms Between Head and Neck Neoplasms and Aging

Objective: This study aims to explore shared key genes between head and neck neoplasm (HNN) and aging. Methods: Using single-cell RNA sequencing data of peripheral blood from HNN patients, aging individuals, and healthy controls, we identified cross-group co-expressed, downregulated cell subpopulations as core targets. Integrated pseudotime trajectory analysis and intercellular communication modeling were employed to investigate the dynamic evolution and functional interaction patterns of these subpopulations. Differentially expressed genes were identified, followed by Mendelian randomization analysis to assess their causal associations with HNN. Co-localization analysis were performed using GWAS data for HNN and expression quantitative trait loci (eQTL) datasets. Key genes were further subjected to metabolic pathway enrichment analysis. Results: T cell subsets were found to be significantly represented in both HNN and aging individuals. Among them, naive CD4(+) T cells was down-regulated in both groups, leading to the identification of 24 differentially expressed genes. Mendelian randomization studies have shown that CCR , LEF1 , NOSIP and FHIT have causal relationships with HNN. In the validation phase, however, only FHIT was retained, for which co-localization analysis revealed limited evidence of a shared causal variant between the GWAS and eQTL signals (H4 = 0.01). The metabolic enrichment highlighted metabolic pathways associated with these genes. Conclusions: This study identified naive CD4(+) T cells downregulation as a shared feature of HNN and aging and highlighted: CCR , LEF1 , NOSIP and particularly FHIT as potential molecular links. These findings provide novel insights into the intersection of aging and tumorigenesis, offering potential targets for combined therapeutic strategies.