A closed-loop comprehensive analysis of global burden data, future projections, risk factors, and molecular mechanisms on nasopharyngeal carcinoma

Background: Nasopharyngeal carcinoma (NPC), a frequent malignant tumor, exhibits a high propensity for both metastasis and recurrence. This study provided a comprehensive analysis of the burden, risk factors, and potential molecular mechanisms of NPC. Methods: Utilizing data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we analyzed NPC burden in relation to age, sex, risk factors, and the sociodemographic index (SDI). The average annual percent change (AAPC) was computed through joinpoint regression. To assess causal links between risk factors and NPC, we employed two-sample Mendelian randomization (MR). Future NPC incidence trends (2022–2050) were projected using the Bayesian age–period–cohort model. We also elucidated the molecular mechanisms that trigger NPC by a bioinformatics analysis. Results: Global NPC mortality (AAPC: −1.817) and disability-adjusted life years (DALYs) rates (AAPC: −1.932) declined from 1990 to 2021. However, rising prevalence (AAPC: +0.317) and persistent high burden in East/Southeast Asia [e.g., Malaysia age-standardized incidence rate (ASIR): 6.09/100 000]. Socioeconomic disparities are widening, with low-SDI regions experiencing slower burden reduction. Projections suggest continued ASIR decline to 1.08/100 000 by 2050. MR analysis confirms smoking as a causal risk [current smokers odds ratio (OR) = 3.10; former smokers OR = 7.00, compared to never smoking], while Secretoglobin family 1A member 1 (SCGB1A1) downregulation emerges as a key mechanistic link-driving immunosuppression via Th2/Treg infiltration and hub genes (CXCL11, CD19). Conclusion: We innovatively constructed a closed-loop on NPC by multiple bioinformatic techniques. Global NPC mortality and DALYs have significantly declined, while this progress is counterbalanced by a rising prevalence and persistently high burden in East/Southeast Asia. Smoking was detected as a strong causal risk factor for NPC, while SCGB1A1 downregulation served as a novel key molecular driver of NPC pathogenesis.