Integrative Genetic and Functional Analysis Identifies the Asparagine–SLC38A2 Axis in Esophageal Squamous Cell Carcinoma

Metabolic reprogramming is a hallmark of cancer, yet the relationships between specific circulating metabolites and esophageal squamous cell carcinoma (ESCC) remain unclear. This study aimed to investigate circulating metabolites potentially associated with ESCC risk and explore their biological relevance through an integrative approach. We employed two‐sample Mendelian randomization (MR) integrating genome‐wide association data from Japanese population, followed by multi‐omics profiling, single‐cell transcriptomic analysis, and in vitro functional validation. MR analyses provided suggestive evidence supporting a potential association between genetically proxied circulating asparagine levels and increased ESCC risk. Asparagine biosynthetic enzymes were enriched in proliferative epithelial cells, while the transporter SLC38A2 was upregulated in invasive epithelial cells and cancer‐associated fibroblasts (CAFs), and was associated with transcriptional programs related to epithelial‐to‐mesenchymal transition, immunosuppression, and extracellular matrix remodeling. Notably, SLC38A2 overexpression in tumor tissues was associated with worse overall survival. Functional assays showed that exogenous asparagine increased SLC38A2 expression and promoted ESCC cell proliferation, invasion, and CAF migration. Collectively, these findings provide convergent genetic, transcriptomic, and functional evidence implicating the asparagine–SLC38A2 axis in ESCC biology. SLC38A2 may represent a mechanistically relevant metabolic vulnerability that warrants further preclinical investigation.