Abstract
BACKGROUND: This Mendelian randomization (MR) study aimed to investigate bidirectional causal relationships between genetically predicted iron homeostasis, mitochondrial function, and the risk of laryngeal and hypopharyngeal cancers. METHODS: Summary-level data were extracted from genome-wide association studies (GWAS) of iron status, mitochondrial function, laryngeal and hypopharyngeal cancers were analyzed. Two-sample MR analyses were performed using inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger regression. Sensitivity analyses incorporated MR-Egger intercept, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Cochran's Q test, and leave-one-out validation. RESULTS: MR analysis identified a significant association between the mitochondrial sirtuin-5 (NAD-dependent protein deacylase) and the elevated risk of hypopharyngeal cancer (OR = 2, 95% CI: 1.06-3.76, P = 0.03). Reverse MR analyses demonstrated that larynx cancer inversely correlated with transferrin saturation (OR = 0.992, 95% CI: 0.987-0.998, P < 0.001) and persulfide dioxygenase ETHE1 (OR = 0.95, 95% CI: 0.92-0.98, P < 0.001). In addition, no causal effect of iron status on the risk of laryngeal and hypopharyngeal cancers (All P > 0.05). Sensitivity analyses confirmed results robustness with no evidence of pleiotropy and heterogeneity. CONCLUSION: Our findings reveal a novel pathogenic role of sirtuin-5 in hypopharyngeal cancer, suggesting its potential as a therapeutic target. Conversely, laryngeal cancer might slightly affect transferrin saturation and ETHE1, indicating their utility as diagnostic markers for laryngeal cancer. Future mechanistic studies are warranted to elucidate these complex associations.