Multidimensional investigation of thyroid hormones and prostate cancer: insights from NHANES, Mendelian randomization, genetic markers, and bioinformatics analyses.

BACKGROUND

Prostate cancer remains a major global health burden for men, with its incidence and mortality steadily rising. Thyroid hormones, critical regulators of metabolism and cell growth, have been implicated in tumorigenesis, yet their specific role in prostate cancer risk remains unclear. This study systematically investigates the relationship between thyroid hormones and prostate cancer using multidimensional approaches.

METHODS

A three-phase study design was employed: (1) A cross-sectional analysis of The National Health and Nutrition Examination Survey (NHANES) data to examine thyroid hormone levels (FT3 and T3) and prostate cancer risk; (2) Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data to explore causal relationships; (3) Bioinformatics analyses to annotate key Single Nucleotide Polymorphism(SNPs), identify related genes, and assess their biological roles in prostate cancer.

RESULTS

Observational analysis revealed significantly lower FT3 and T3 levels in high-risk prostate cancer patients, with adjusted models confirming an inverse association (p < 0.001). MR analysis supported a causal relationship between thyroid hormone replacement therapy and reduced prostate cancer risk (b < 0, p < 0.05). Four key genes-ADM5, INPP5B, NEURL4, and TYK2-were identified as downregulated in prostate cancer tissues, with prognostic and immune regulatory implications.

CONCLUSIONS

Thyroid hormones exhibit a protective role against prostate cancer. ADM5, INPP5B, NEURL4, and TYK2 emerge as potential biomarkers and therapeutic targets, warranting further mechanistic and clinical validation.