Work

Mediation of sphingolipid metabolism on the relationship between human nitrosamines exposure and esophageal cancer risk

Year: 2026

Type: article

Abstract: Although nitrosamines are known as potent carcinogenic contaminants with multisystem toxicity, the metabolic mechanisms driving esophageal carcinogenesis under multi-nitrosamine co-exposure remain poorly understood. This molecular epidemiological study sought to identify dynamic metabolic signatures mediating nitrosamine-associated esophageal squamous cell carcinoma (ESCC) risk. We quantified urinary levels of nine nitrosamines in participants across esophageal lesion stages (RE/BCH, DYS, ESCC) and employed UPLC-MS/MS metabolomics to investigate exposure-response relationships and mediation effects of key metabolites. Distinct stage-specific nitrosamine profiles were observed. Sphingolipid metabolism emerged as a critical pathway in ESCC pathogenesis: DH-SPH, DH-S1P, and S1P were positively associated with increased risk, while SPH and the SPH/S1P ratio demonstrated protective effects. Mediation analysis revealed metabolite-specific pathways, with DH-S1P acting as a shared mediator in NDphA-, NMEA-, and NPIP-induced ESCC pathways, and S1P mediating NMEA-associated progression from RE/BCH to ESCC. Sensitivity analyses indicated differential robustness across pathways. E-value assessment revealed that NDphA-related pathways exhibited high resistance to unmeasured confounding (E-value > 2). Critical ρ analysis indicated that DH-S1P-mediated pathways in ESCC exhibited high credibility (ρ thresholds ≈ 0.3), and SPH/S1P-mediated pathways yielded conservative effect estimates. ROC analysis with bootstrapping validation suggested the potential discriminative ability of sphingolipid metabolites: S1P showed promise in distinguishing across the disease spectrum, and a combined panel demonstrated improved performance for ESCC prediction and nitrosamine exposure discrimination in this study population. Collectively, these findings underscore sphingolipid dysregulation as a key associative mediator linking nitrosamine exposure to ESCC progression, and support their potential as candidate biomarkers for early screening and exposure monitoring in high-risk populations. However, due to the cross-sectional design and absence of external validation, these findings await confirmation in prospective and functional studies.

Source: Scientific Reports

DOI: 10.1038/s41598-026-48589-x