Abstract
BACKGROUND: Gastric precancerous lesions (GPL) represent a heterogeneous, multi-stage process that involves transition from a benign to a malignant state. To optimize prevention and intervention strategies, accurate methods must clearly distinguish between precancerous stages and predict progression risks at early stages. METHODS: The metabolomic profiles of 188 GPL tissues and matched normal tissues were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry. Both multivariate and univariate statistical analyses were used to identify metabolomic features differentiating normal, atrophic, and intestinal metaplasia states in the stomach, followed by preliminary functional validation. RESULTS: From experiments conducted on two cohorts, we established a reliable clinical gastric tissue metabolomic map, which clearly distinguished between normal, atrophic, and intestinalized gastric tissues. We then identified metabolic biomarkers that differentiated various GPL stages. Furthermore, key metabolites were validated in in vitro studies. Relative acyl group and glycerophospholipid abundance was higher in normal gastric tissue when compared to GPL, whereas organic acids were more prevalent in precancerous tissues than in normal tissues. A combination of glycerophosphocholine, tiglylcarnitine, malate, sphingosine, and γ-glutamylglutamic acid may serve as powerful biomarkers to distinguish normal tissue from GPL. CONCLUSION: We used ultra-high-performance liquid chromatography with tandem mass spectrometry to effectively characterize metabolomic profiles in clinical gastric tissue samples. Key metabolites were identified and validated using targeted metabolomics. This study identified the metabolomic profiles of gastric tissues with atrophy and intestinal metaplasia of the gastric mucosa, uncovering and preliminarily validating key metabolites that may be used to assess high-risk populations and diagnose GPL, potentially advancing targeted gastric cancer prevention and treatment efforts.