3‐Indoxyl Sulfate and O ‐Acetylcarnitine Are Potential Novel Biomarkers for Early Diagnosis of Esophageal Cancer

Esophageal cancer is the seventh most common cancer worldwide, and early detection is crucial for improving long-term survival. However, reliable noninvasive biomarkers for early-stage disease remain limited. In this study, we aimed to identify novel biomarkers for early-stage esophageal cancer through comprehensive metabolomic analyses of plasma and urine samples from patients and healthy individuals. Metabolomic profiling revealed that 3-indoxyl sulfate (3-IS) was consistently elevated in both plasma and urine of esophageal cancer patients. As esophageal cancer cells do not directly produce 3-IS, its elevation may reflect cancer-associated systemic metabolic alterations. O-acetylcarnitine (O-AC) was identified as the most significantly increased metabolite in plasma, and in vitro analyses suggested a possible association with tumor-related metabolic changes. Receiver operating characteristic analyses (ROC) demonstrated that the combined plasma and urinary 3-IS model achieved an area under the curve (AUC) of 0.863 in Stage I/II disease, whereas plasma O-AC achieved an AUC of 0.902. Bootstrap resampling provided internal validation; however, the discovery and evaluation were performed within the same single-center cohort. These results suggest that 3-IS and O-AC are promising candidate biomarkers that distinguish patients with esophageal cancer from healthy individuals, but further validation of their disease specificity and diagnostic performance is required in independent multicenter cohorts including clinically relevant disease-control groups.