Introduction
Esophageal cancer (EC) exhibits a disproportionate burden in low- and middle-income regions. Magnesium, a critical regulator of metabolic and inflammatory pathways, has been implicated in chronic diseases such as diabetes and cardiovascular disorders. Preclinical studies suggest that magnesium deficiency promotes oxidative stress and systemic inflammation, processes central to cancer progression. However, evidence directly linking magnesium metabolism disorders with esophageal cancer risk remains limited. The Magnesium Depletion Score (MDS), a validated tool integrating diuretic use, proton pump inhibitors, renal dysfunction, and heavy alcohol consumption, offers a novel approach to evaluate magnesium status. The study aims to elucidate the potential mechanisms by which magnesium metabolism may influence the development of esophageal cancer and to provide a scientific basis for future preventive and intervention strategies.
Aims & Methods
This prospective cohort study included 450,700 UK Biobank participants. The Magnesium Depletion Score (MDS) incorporated diuretic use, proton pump inhibitors, renal function (eGFR-based), and heavy alcohol consumption, categorized as low (0–1), moderate (2), or high (3–5). Multivariable Cox proportional hazards models, adjusted for demographics, socioeconomic factors, BMI, smoking, and alcohol use, assessed associations between MDS and esophageal cancer (EC) incidence (ICD-10: C15) and subtypes. Sensitivity analyses excluded participants with <1–3 years of follow-up. Mediation analyses evaluated inflammatory/metabolic biomarkers (e.g., CRP, HbA1c). Subgroup analyses explored effect modification by age, sex, and lifestyle factors, while restricted cubic splines tested nonlinear relationships. Analyses adhered to STROBE guidelines and utilized R v4.2.3.
Results
Among 450,700 participants (54% female, mean age 56.6 years), 1,572 developed esophageal cancer (EC: 645 adenocarcinomas [EAC], 275 squamous cell carcinomas [ESCC], 905 lower EC). EC cases were predominantly male, older (mean +4.8 years vs. non-EC), and exhibited higher Magnesium Depletion Score (MDS), BMI, smoking rates, and socioeconomic deprivation. EAC patients were more likely overweight/obese (BMI >25), while ESCC patients had higher smoking rates and normal BMI.
Higher MDS was significantly associated with increased EC risk (continuous MDS: HR=1.186, 95% CI:1.102–1.277, P<0.001). Compared to low MDS (0–1), moderate (2) and high MDS (3–5) groups showed 29.6% (HR=1.296, P=0.001) and 63.5% (HR=1.635, P<0.001) higher EC risk, respectively. Similar trends were observed for EAC (HR=1.277, P<0.001) and lower EC (HR=1.158, P=0.003). Sensitivity analyses excluding early-diagnosis cases (1–3 years) confirmed robustness. Associations persisted after adjusting for diabetes, hypertension, and H. pylori.
Stratified analyses revealed stronger MDS-EC associations in males, smokers, alcohol consumers, and overweight/obese individuals (BMI>25). MDS did not correlate with all-cause mortality in EC patients (HR=0.963, P=0.370). Mediation analyses identified inflammatory (C-reactive protein: 1.40%, P=0.013; neutrophils: 4.50%, P=0.003) and metabolic biomarkers (HbA1c: 0.91%, P=0.033; glucose: 0.38%, P=0.047) as partial mediators.
Conclusion
In summary, this study demonstrates a significant positive association between MDS and the risk of esophageal cancer, with an especially pronounced impact observed among overweight or obese individuals, males, and alcohol consumers. The findings support the hypothesis that magnesium metabolism may influence esophageal cancer through multiple mechanisms, including inflammation, metabolic abnormalities, and immune dysfunction.