Analysis of toxicity and mechanisms of aspartame in kidney stones with network toxicology and molecular docking strategy

Aspartame, an artificial sweetener, has been implicated in the formation of kidney stones, although the underlying mechanisms remain poorly understood. This study aims to analyze the toxicity of aspartame on kidney stone development using network toxicology and molecular docking strategies. We used ChEMBL, SwissTargetPrediction, and STITCH databases to identify 145 unique targets of aspartame action, and GeneCards and OMIM databases to identify 776 unique targets related to kidney stones. Integration of these datasets revealed 19 common targets for aspartame-induced kidney stones. A Protein-Protein Interaction (PPI) network was constructed utilizing the STRING database, and the topological properties of this network were evaluated using Cytoscape software. This analysis revealed five key targets: ACE, IL1B, REN, CASP3, and NOS3. To further understand the biological significance of these targets, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the DAVID database. The results indicated that core targets are primarily involved in endocrine processes, endopeptidase activity, and aspartic-type endopeptidase activity. Notably, signaling pathways such as the renin-angiotensin system (RAS) demonstrated significant associations with aspartame-related toxicity. Molecular docking analysis using Autodock Vina revealed a positive affinity between the proteins and aspartame. Molecular Dynamics (MD) simulations revealed stable interactions and optimized binding conformations for all targets, suggesting significant roles for specific residues like GLU384 in ACE, ARG341 in CASP3, ARG183 in NOS3, and ARG98 in IL1B. This study successfully identifies and characterizes the key molecular targets and pathways associated with aspartame-induced kidney stones, providing a foundational understanding of the underlying biological mechanisms. Additional experiments are necessary to verify these findings and explore therapeutic approaches targeting these pathways.