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Background <p>Aspartame (APM), a widely used sweetener, has been linked to cancers, yet its molecular impact on metabolic dysfunction-associated steatotic liver disease (MASLD) and subsequent hepatocellular carcinoma (HCC) remains undefined. We integrated network toxicology, bulk RNA-seq and docking to map the mechanism.</p> Methods <p>APM targets were retrieved from ChEMBL, STITCH and SwissTargetPrediction. MASLD and HCC RNA-seq data from GEO were used to call differentially expressed genes(DEGs). WGCNA identified disease modules and hub genes. Intersection of APM targets, DEGs and hubs defined core genes for GO/KEGG and PPI analyses. CytoHubba (DMNC, EPC, Degree, MCC), LASSO, RF and SVM-RFE shortlisted key genes, and docking verified APM binding.</p> Results <p>Twelve genes intersected across APM, MASLD and HCC datasets. Enrichment supports a “dual-track” mechanism: APM-MASLD targets suppress bile-acid export, impair lipid clearance and fuel steatosis; MASLD-HCC targets jointly activate TNF/IL-17 and chemical-carcinogenesis pathways, indicating chronic inflammation bridges steatosis to cancer; APM-HCC targets map to p53, nuclear-receptor and xenobiotic-response networks, revealing APM hijacks receptor signalling to impose proliferative stress that, coupled with p53 loss, drives clonal selection. Machine-learning nominated EGR1 and PTGS2 as top diagnostic genes (AUC &gt; 0.7); docking showed high-affinity APM binding (–7.1 and–7.9&#xa0;kcal mol⁻¹, respectively), identifying them as key relays in APM-induced HCC.</p> Conclusions <p>EGR1 and PTGS2 are central nodes through which APM precipitates MASLD and accelerates progression to HCC. We propose a “dual-track” oncogenic paradigm: Track A follows the canonical MASLD-HCC axis (bile-acid retention - lipid deposition - TNF/IL-17-driven ROS-mutational amplification), whereas Track B allows APM, via PTGS2/EGR1, to usurp gate-keeper proteins governing proliferation and apoptosis, initiating malignant programming before overt steatosis develops. These findings provide mechanistic insight into APM-related hepatocarcinogenesis, nominate tractable diagnostic biomarkers and therapeutic targets, and inform future re-evaluation of APM carcinogenicity classifications.</p> Graphical Abstract <p></p>

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Aspartame drives the continuous progression from MASLD to HCC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Xusheng Zhang,
  • Rong Tan,
  • Yongxin Ma,
  • Jian Fei Zhang,
  • Qi Wang,
  • Bendong Chen

摘要

Background

Aspartame (APM), a widely used sweetener, has been linked to cancers, yet its molecular impact on metabolic dysfunction-associated steatotic liver disease (MASLD) and subsequent hepatocellular carcinoma (HCC) remains undefined. We integrated network toxicology, bulk RNA-seq and docking to map the mechanism.

Methods

APM targets were retrieved from ChEMBL, STITCH and SwissTargetPrediction. MASLD and HCC RNA-seq data from GEO were used to call differentially expressed genes(DEGs). WGCNA identified disease modules and hub genes. Intersection of APM targets, DEGs and hubs defined core genes for GO/KEGG and PPI analyses. CytoHubba (DMNC, EPC, Degree, MCC), LASSO, RF and SVM-RFE shortlisted key genes, and docking verified APM binding.

Results

Twelve genes intersected across APM, MASLD and HCC datasets. Enrichment supports a “dual-track” mechanism: APM-MASLD targets suppress bile-acid export, impair lipid clearance and fuel steatosis; MASLD-HCC targets jointly activate TNF/IL-17 and chemical-carcinogenesis pathways, indicating chronic inflammation bridges steatosis to cancer; APM-HCC targets map to p53, nuclear-receptor and xenobiotic-response networks, revealing APM hijacks receptor signalling to impose proliferative stress that, coupled with p53 loss, drives clonal selection. Machine-learning nominated EGR1 and PTGS2 as top diagnostic genes (AUC > 0.7); docking showed high-affinity APM binding (–7.1 and–7.9 kcal mol⁻¹, respectively), identifying them as key relays in APM-induced HCC.

Conclusions

EGR1 and PTGS2 are central nodes through which APM precipitates MASLD and accelerates progression to HCC. We propose a “dual-track” oncogenic paradigm: Track A follows the canonical MASLD-HCC axis (bile-acid retention - lipid deposition - TNF/IL-17-driven ROS-mutational amplification), whereas Track B allows APM, via PTGS2/EGR1, to usurp gate-keeper proteins governing proliferation and apoptosis, initiating malignant programming before overt steatosis develops. These findings provide mechanistic insight into APM-related hepatocarcinogenesis, nominate tractable diagnostic biomarkers and therapeutic targets, and inform future re-evaluation of APM carcinogenicity classifications.

Graphical Abstract