Saccharin Aggravates Eosinophilic Esophagitis via MAPK3 Interaction: A Network Toxicology and Machine Learning Study With SPR Analysis

This original research investigated the potential role of the artificial sweetener saccharin in exacerbating eosinophilic esophagitis (EoE), a chronic immune-mediated inflammatory disease of the esophagus. Using an integrated approach combining network toxicology, weighted gene co-expression network analysis, machine learning algorithms (LASSO and SVM-RFE), molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) validation, the study identified MAPK3 as a key pathogenic target through which saccharin may aggravate EoE. Among six candidate genes linked to EoE, saccharin demonstrated strong and stable binding affinity to MAPK3, confirmed experimentally by SPR with a dissociation constant of 45.0 μM. Mechanistically, saccharin–MAPK3 interaction may activate MAPK/ERK signaling pathways that promote Th2-type inflammation, epithelial barrier disruption, and eosinophil recruitment. The findings highlight saccharin as a previously unrecognized dietary risk factor for EoE and underscore the need for re-evaluating artificial sweetener safety in susceptible populations.