Iron status and cancer risk across 14 cancers: evidence from cross-sectional analyses and a three-stage Mendelian randomization

OBJECTIVE: The relationship between systemic iron status and cancer risk remains debated, with inconsistent findings from observational studies. To provide robust evidence, we systematically assessed four iron status markers-ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity-in relation to 14 cancers and explored potential mediating pathways. METHOD: We employed a cross-sectional analysis of 7,887 European participants from the National Health and Nutrition Examination Survey (NHANES) and applied a three-stage Mendelian randomization (MR) framework. The MR analyses included a two-sample MR analysis to validate associations, a multivariable MR analysis to identify independent effects, and a mediation analysis to dissect potential mediating mechanisms. An MR-phenome-wide association study (MR-PheWAS) was performed to assess potential adverse effects of systemic iron modulation. RESULTS: In the cross-sectional study, higher ferritin levels were associated with increased ovarian cancer risk (OR: 2.23; 95% CI: 1.56-3.17, P < 0.01), higher serum iron with liver cancer risk (OR: 4.15; 95% CI: 1.95-8.68, P < 0.01), and higher TSAT with cervical cancer risk (OR: 3.79; 95% CI: 2.58-4.25, P < 0.01). Two-sample MR analysis confirmed these associations, which remained robust in replication cohorts and multivariable MR adjusting for smoking, alcohol use, body mass index, diabetes, and age. Mediation analyses revealed that glycine partially mediated the ferritin-ovarian cancer link, mannose and total bilirubin mediated the serum iron-liver cancer association, and cortisone and carnitine mediated the TSAT-cervical cancer relationship. MR-PheWAS identified hemoglobin-related traits but no significant adverse effects. CONCLUSION: Genetic evidence suggests that iron status is linked to risks of ovarian (though potentially influenced by smoking), liver, and cervical cancer through metabolic pathways. These findings generate novel hypotheses identifying iron as a modifiable determinant of cancer susceptibility and underscore the need for further investigation into iron modulation as a potential strategy for cancer prevention and therapy.