Risk of serum circulating environmental chemical residues to esophageal squamous cell carcinoma: a nested case-control metabolome-wide association study.

Esophageal squamous cell carcinoma (ESCC) is the primary histological subtype of esophageal carcinoma, yet research on environmental exposure risks and associated metabolic alterations preceding ESCC is limited. In a nested case-control cohort of 396 adults (199 diagnosed with ESCC and 197 healthy controls (HC)), we combined exposomics and metabolomics to assess circulating chemical residues and early serum metabolic changes linked to ESCC risk. A cell experiment further evaluated the proliferative impact of 1H,1H,2H,2H-perfluorooctanesulfonic acid (6:2 FTS), identifying it as a risk factor for ESCC, primarily through lipid metabolism-related chronic inflammation. Significant metabolic disruptions were observed in ESCC cases, characterized by increased carnitines, phosphatidylcholines (PCs), and triglycerides (TGs) alongside reduced lysophosphatidylcholines (LPCs) and ether lysophosphatidylcholines (LPC-Os). An early-warning biomarker panel, including glutamic acid, methionine, choline, LPC-O 18:0, TG (14:0_18:2_20:5), and PC (18:0_20:4)/LPC 18:0, showed improved predictive capacity when combined with 6:2 FTS. Metabolome-exposome-wide association studies largely confirmed 6:2 FTS as a potential ESCC risk factor through lipid mediation. This study offers novel insights for ESCC prevention and early diagnosis through a combined biomarker panel integrating metabolic and environmental risk indicators.