Integrated metabolomics and network pharmacology to decipher habitat-driven metabolic diversity and α-glucosidase inhibitory mechanisms in guava leaves

Guava (Psidium guajava L.) leaves are valuable functional ingredients; however, evidence linking environmental origin to metabolite-resolved bioactivity remains limited. This study investigated leaves from five Bolivian sites across two ecological regions. While the total phenolic content remained stable, the total flavonoid content and α-glucosidase inhibition varied significantly across origins. Widely targeted LC-MS/MS annotated 1230 phenolic features and 753 differential metabolites, revealing an environmental-driven metabolic trade-off: high-irradiance lowlands accumulate lipophilic aglycones, whereas rainforests sequester hydrophilic flavonoid glycosides. Chemometrics revealed origin-dependent chemotypes: Amazonian extracts are glycoside-rich with strong enzymatic inhibition, whereas Lowland extracts are aglycone-enriched for radical scavenging. Network pharmacology and molecular docking prioritized norwogonin, predicting high TNF affinity (-10.1 kcal/mol) and AGE-RAGE axis targeting (e.g., AGER, AKT1, MAPK14). These predictions require experimental validation. Resolving the chemical heterogeneity of Bolivian guava, this work proposes a dual-chemotype classification, providing a robust framework for the strategic sourcing and standardization of functional food resources.