L-pentahomoserine correlates with therapy outcome in esophageal cancer and promotes metabolic adaptations that support cell survival under nutrient-deprived conditions

Abstract Esophageal adenocarcinoma (EAC) is the sixth-leading cause of cancer-related death. Although pyrimidine analogue-based neoadjuvant and adjuvant therapies are widely used, patient responses remain variable. Emerging evidence indicates that bacteria-derived metabolites influence tumor biology and therapy outcomes. To identify non-canonical plasma metabolites linked to cancer biology, we performed correlation analyses between untargeted metabolomics profiles and overall survival. This approach revealed a bacterial metabolite called L-pentahomoserine, or L-2-amino-5-hydroxypentanoic acid (L-2A5HPA), to be positively associated with overall survival. Notably, L-2A5HPA promoted cell survival under nutrient limitation by redirecting glucose metabolism towards aspartate and pyrimidine biosynthesis. In vitro, L-2A5HPA uptake varied among cell lines and was controlled by stereospecific transporters. Furthermore, metabolic profiling in mouse models of liver cancer showed different levels of L-2A5HPA and a strong correlation with pyrimidine intermediates, dihydroorotate and orotate. The link between L-2A5HPA, pyrimidine nucleotide metabolism, and cell survival provides mechanistic insight into its association with patient outcome. Our findings position L-2A5HPA as a metabolite with potential to become a prognostic biomarker for EAC and underscores its role in metabolic adaptation under nutrient-deprived conditions.