FeatureMAP enables network-guided interpretation of untargeted metabolomics

Abstract

Untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics generates thousands of features, but incomplete metabolite annotation and reliance on predefined pathways limit their biological interpretation. Here we present FeatureMAP, an LC-MS feature-centric computational framework that integrates multi-evidence metabolite annotation, network-guided refinement, metabolic module discovery, and structured large language model-based functional interpretation. Across ten public datasets, FeatureMAP improved MS1-based metabolite candidate prioritization while reducing annotation redundancy. In semi-synthetic benchmarks, FeatureMAP recovered coordinated metabolic perturbations, achieving 92% recovery of a simulated perturbation, and distinguished concurrent metabolic processes. Controlled benchmarks further evaluated functional interpretation under competing metabolite-level signals. Based on FeatureMAP, we additionally developed PhenoMAP, a phenotype-aware knowledge graph comprising 12,929 dysregulated metabolic modules from 501 human metabolomics studies spanning 326 phenotypes. Module-level comparisons revealed reproducible metabolic similarities across independent studies and biologically supported relationships among phenotypes. Application to Alzheimer's disease cerebrospinal fluid and cellular datasets identified convergent membrane-lipid alterations and implicated galactose-linked glycosphingolipid remodeling. Together, FeatureMAP and PhenoMAP enable network-grounded interpretation of incompletely annotated LC-MS metabolomics data and systematic investigation of metabolic dysregulation across biological conditions.