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

TL;DR

Saccharin may worsen eosinophilic esophagitis by interacting with a key protein, MAPK3, suggesting a new dietary risk factor.

Contribution

This study identifies saccharin as a novel dietary aggravator of EoE through direct interaction with MAPK3.

Findings

Saccharin binds to MAPK3, CPS1, and HS3ST1, which are linked to EoE.

SPR analysis confirmed direct binding of saccharin to MAPK3.

Saccharin activates pro-inflammatory pathways via MAPK3, exacerbating EoE.

Abstract

The potential role of artificial sweeteners in eosinophilic esophagitis (EoE) remains poorly understood. This study aimed to investigate the molecular mechanism by which saccharin might exacerbate EoE. We integrated network toxicology with machine learning approaches to identify core pathogenic genes of EoE. The interactions between saccharin and the predicted targets were validated via molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR). Our analysis identified MAPK3, CPS1, and HS3ST1 as potential EoE‐related targets of saccharin. Molecular docking demonstrated strong binding affinities between saccharin and these proteins, which was confirmed by stable binding via molecular dynamics simulations. Further SPR analysis revealed that saccharin binds directly to MAPK3. This study demonstrated that saccharin potentially aggravates EoE by directly targeting MAPK3 to activate pro‐inflammatory pathways, highlighting a novel dietary risk factor and underscoring the need for a safe reevaluation for susceptible populations.

This study provides a novel molecular perspective on the role of dietary factors in EoE pathogenesis. We establish saccharin as a key aggravating factor for EoE and highlight MAPK3 as a compelling therapeutic target. Our findings suggest that controlling saccharin intake represents a direct and beneficial dietary management strategy for EoE. We offer crucial evidence for re‐evaluating the safety of saccharin in susceptible populations, bridging food additive exposure to EoE risk.

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