ANPEP as a potential mediator linking aspartame exposure to MAFLD: insights from network toxicology and multi-omics
Long Xu1, Chi Zhang1, Shengliang Xin1
1Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China.
Background:
Aspartame (APM) is a widely consumed artificial sweetener that has recently been implicated in the pathogenesis of metabolic disorders. However, the molecular mechanisms linking APM to metabolic-associated fatty liver disease (MAFLD) remain poorly understood.
Materials And Methods:
This study employed a comprehensive analytical strategy, integrating network toxicology, molecular docking, molecular dynamics simulations, machine learning, bulk RNA sequencing and single-cell transcriptomics, Mendelian randomization, and histological validation, to systematically investigate APM-associated molecular targets and their potential role in MAFLD.
Results:
The ADMETlab3.0 prediction indicated that APM exhibits strong hepatotoxic potential. Network toxicology analysis identified 80 overlapping genes, among which ANPEP demonstrated the lowest binding energy to APM (-8.2 kcal/mol). Molecular dynamics simulations further confirmed the stability of this interaction. Bulk RNA-seq data revealed that ANPEP was significantly upregulated in MAFLD liver tissues (P < 0.001) and achieved robust diagnostic performance (AUC = 0.84, 95% CI: 0.69-1.00, P < 0.01). In mouse models, Anpep expression was significantly elevated (P = 0.005). Mendelian randomization analysis indicated that elevated ANPEP levels were significantly associated with a higher risk of MAFLD (OR = 1.069, 95% CI: 1.017-1.124, P = 0.008). Single-cell sequencing and immunofluorescence analyses consistently confirmed that ANPEP was predominantly localized in CD68⁺ myeloid cells and was markedly upregulated as early as the fibrotic initiation stage of MAFLD (P < 0.01).
Conclusion:
ANPEP was identified as a potential target that links aspartame exposure to MAFLD, and was further associated with inflammation, lipid dysregulation, and fibrosis. These findings suggest that aspartame may not represent a safe strategy for weight management and could increase the risk of liver injury and MAFLD progression.
Insights
Aspartame (APM) exposure may increase the risk of metabolic-associated fatty liver disease (MAFLD) by upregulating ANPEP, a protein linked to liver inflammation and fibrosis. This suggests APM is not a safe weight management strategy.
Area of Science:
- Biochemistry
- Toxicology
- Genomics
Background:
- Aspartame (APM) is a common artificial sweetener linked to metabolic disorders.
- Molecular mechanisms connecting APM to metabolic-associated fatty liver disease (MAFLD) are not well understood.
Purpose of the Study:
- To investigate the molecular targets linking aspartame exposure to MAFLD.
- To elucidate the role of these targets in the pathogenesis of MAFLD.
Main Methods:
- Integrated network toxicology, molecular docking, molecular dynamics, machine learning, and transcriptomics.
- Mendelian randomization and histological validation were employed.
- Bulk and single-cell RNA sequencing were used to analyze gene expression.
Main Results:
- Aspartame (APM) showed significant hepatotoxic potential.
- ANPEP was identified as a key molecular target, showing strong binding with APM and upregulation in MAFLD liver tissues and mouse models.
- Elevated ANPEP levels were significantly associated with increased MAFLD risk and were localized in myeloid cells during early fibrotic stages.
Conclusions:
- ANPEP is a potential mediator linking aspartame exposure to MAFLD, inflammation, lipid dysregulation, and fibrosis.
- Aspartame may pose risks for liver injury and MAFLD progression, questioning its safety for weight management.
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