Comprehensive metabolic profiling uncovers early variation and biomarkers of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a poor prognosis, primarily due to late-stage diagnosis. This study aimed to elucidate the metabolic alterations associated with the development and early progression of ESCC and to identify potential biomarkers for its early diagnosis. Using two independent cohorts comprising 245 individuals in total, with 161 individuals in cohort 1 (a cross-sectional cohort) and 84 LGIN patients in cohort 2 (a follow-up cohort) at baseline, untargeted metabolomic profiling of 329 serum samples revealed 1,431 metabolites. Significant dysregulation was observed in steroid hormone biosynthesis, primary bile acid biosynthesis, and glycine, serine, and threonine metabolism. Combining metabolomics and transcriptomics data, multi-omics integration identified key metabolites and genes driving these pathways, particularly in early tumorigenesis. Furthermore, 9 blood-based metabolites were identified as potential non-invasive biomarkers for early ESCC detection and achieved high predictive accuracy. The findings provide critical insights into the metabolic underpinnings of ESCC progression and underscore the value of blood-based metabolite biomarkers for early diagnosis.