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 comprehe...
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Elsevier
2025-04-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325004257 |
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| author | Ni-ren Li Yi-xuan Zeng Yu-feng Gu Pai Xie Bing-ying Deng Si-fan Lu Wang-an Li Yi Liu |
| author_facet | Ni-ren Li Yi-xuan Zeng Yu-feng Gu Pai Xie Bing-ying Deng Si-fan Lu Wang-an Li Yi Liu |
| author_sort | Ni-ren Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7af464a4f83f4fbda22faa1d4e1f5896 |
| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-7af464a4f83f4fbda22faa1d4e1f58962025-08-20T02:09:07ZengElsevierEcotoxicology and Environmental Safety0147-65132025-04-0129411808910.1016/j.ecoenv.2025.118089Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insightsNi-ren Li0Yi-xuan Zeng1Yu-feng Gu2Pai Xie3Bing-ying Deng4Si-fan Lu5Wang-an Li6Yi Liu7Traditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaJiangmen Central Hospital, Jiangmen 529000, PR China; Corresponding author.Traditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR ChinaCollege of Life Science and Chemistry, Hunan University of Technology, PR ChinaTraditional Chinese Pharmacological Laboratory, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0147651325004257Network toxicologyMendelian randomizationMolecular DynamicsCASP1 proteinAspartameliver cancer |
| spellingShingle | Ni-ren Li Yi-xuan Zeng Yu-feng Gu Pai Xie Bing-ying Deng Si-fan Lu Wang-an Li Yi Liu Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights Ecotoxicology and Environmental Safety Network toxicology Mendelian randomization Molecular Dynamics CASP1 protein Aspartame liver cancer |
| title | Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights |
| title_full | Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights |
| title_fullStr | Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights |
| title_full_unstemmed | Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights |
| title_short | Aspartame increases the risk of liver cancer through CASP1 protein: A comprehensive network analysis insights |
| title_sort | aspartame increases the risk of liver cancer through casp1 protein a comprehensive network analysis insights |
| topic | Network toxicology Mendelian randomization Molecular Dynamics CASP1 protein Aspartame liver cancer |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325004257 |
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