Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights

Background

Aspartame is a widely used artificial sweetener in food and beverages. Its safety concerns and potential carcinogenic risks have garnered increasing attention. This study aims to systematically explore the carcinogenic potential and mechanisms of aspartame on the liver through a comprehensive analysis based on network toxicology, mendelian randomization, molecular dynamics and single-cell RNA sequencing.

Methods

ProTox 3.0 and ADMEtlab 2.0 platforms were used to predict the toxicity and drug metabolism levels of aspartame. Network toxicology methods were employed to investigate the pathogenic pathways and mechanisms of aspartame in liver cancer. Mendelian randomization (MR) was used to verify the causal relationship between aspartame’s carcinogenic targets and liver cancer. Furthermore, molecular docking and molecular dynamics (MD) simulations were conducted to explore the binding efficiency and stability of aspartame with the validated targets from MR. Single-cell technology further explores which types of liver cells have the highest expression of CASP1.

Results

Combining the results from two prediction platforms, it was found that aspartame exhibits significant neurological, nephrotoxic, and hepatotoxic effects. Network toxicology results indicated that aspartame promotes the development of liver cancer by affecting multiple key proteins and regulatory factors PTGS2, IL1β and CASP1, in the Necroptosis, NF-κB and TNF signaling pathways. MR was used to discover that among the core targets of aspartame, REN, HLA-A, CASP1, and MME have causal relationships with liver cancer, while CASP1 is a risk factor for liver cancer. The binding affinity of aspartame to these four proteins was investigated by molecular docking, and it was found that the binding to CASP1 was the strongest at −18.45 kJ/mol. MD further verified that over a 50 ns period, the protein-target complex of aspartame and CASP1 exhibited excellent binding stability. Additionally, the single-cell sequencing found that CASP1 is most highly expressed in endothelial cells. In summary, these findings suggested that aspartame may increase the possibility of liver cancer by modulating the CASP1 protein.

Conclusions

This study identifies CASP1 as a potential target for aspartame-induced liver cancer, which is of a significant public health importance. The potential carcinogenic risk of aspartame and reliability need to be re-evaluated. The study provides a new method for assessing the safety of food additives and offers novel scientific insights into the toxicological effects of aspartame. Furthermore, subsequent experimental validation is crucial for further research into the carcinogenic mechanisms of aspartame.