Keywords
HNSCC
Functional enrichment
Immune infiltration
Prognostic biomarkers
Submitted : 2025-09-17
Accepted : 2025-10-02
Published : 2025-10-17
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with a heterogeneous etiology. Circulating total cholesterol (TC), apolipoprotein A-I (ApoA-I), and low-density lipoprotein cholesterol (LDL-C) may influence tumorigenesis via metabolic, inflammatory, and immune pathways. The causal relationship and molecular mechanisms remain unclear. This study systematically evaluated lipid-related genetic variants and HNSCC risk. Methods: Two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) data assessed causal effects of TC, ApoA-I, and LDL-C on head and neck cancer (HNC). Significant single-nucleotide polymorphisms (SNPs) were functionally annotated and subjected to pathway enrichment. Candidate genes were analyzed in GEPIA2, TIMER3.0, and cBioPortal for differential expression (DE), survival, immune infiltration, and clinical stage associations. Results: MR revealed no significant causal effects (P>0.05). Positive effect group SNPs are enriched in cytochrome P450 (CYP450)-mediated xenobiotic metabolism; negative effect group SNPs are enriched in monocarboxylic acid and alcohol metabolism pathways, suggesting protective metabolic adaptation. DE analysis showed ADH1B downregulation and FADS1/2, PARP9, and SEMA7A upregulation. Immune infiltration linked these genes to CD8⁺ T cells, M1/M2 macrophages, regulatory T cells (Treg), cancer-associated fibroblasts (CAF), and NK cells, with ADH1B downregulation associated with immunotherapy response. ALDH1A2, EVI5, and LCAT, though not DE, exhibited prognostic value, with expression increasing in advanced stages. Conclusion: Lipid-related variants may influence HNSCC via opposing mechanisms: CYP450/inflammation versus metabolic adaptation/alcohol pathways. ADH1B and FADS1/2, PARP9, SEMA7A regulate tumor metabolism and immune microenvironment; ALDH1A2, EVI5, and LCAT hold prognostic potential. These findings provide mechanistic insight and candidate molecular targets for HNSCC prediction and intervention.
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