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Updated: Jan 18, 2026
A Biomimetic Model for Liver Cancer to Study Tumor-Stroma Interactions in a 3D Environment with Tunable Bio-Physical Properties
Published on: August 7, 2020
Mechanistic insights into aristolochic acid-induced hepatocellular carcinoma: a multi-dimensional analysis
1School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Key Laboratory of Drugability and Preparation Modification of TCM, Changsha, 410208, China.
Background:
Aristolochic acids (AA) are naturally occurring carcinogens found in traditional herbal medicines derived from Aristolochia species. This study explores the potential link between AA and hepatocellular carcinoma (HCC), aiming to uncover key molecular targets driving AA-induced hepatocarcinogenesis.
Methods:
Toxicogenomic databases were used to identify AA-related toxicological profiles and targets, which were integrated with HCC-associated gene datasets. Protein-protein interaction networks were constructed, followed by enrichment analyses. A multi-machine learning framework was applied to prioritize candidate genes. Bioinformatic validation included immunohistochemistry, survival analysis, and immune infiltration profiling. Compound-protein interactions and structural stability were assessed via molecular docking and molecular dynamics simulations.
Results:
We identified 2378 overlapping genes between AA and HCC. Enrichment analyses revealed significant activation of proteasome, cell cycle, and antigen processing pathways. PSMB4 was prioritized as a core gene, overexpressed in HCC tissues, associated with poor prognosis (HR = 1.69, p < 0.05), and strongly correlated with regulatory T cell and M2 macrophage infiltration. Docking and MD simulations confirmed strong and stable binding (-8.7 kcal/mol) between AA and PSMB4.
Conclusion:
This study establishes a potential mechanistic connection between AA and HCC using an integrated network toxicology and machine learning, offering novel insights into toxicant-driven hepatocarcinogenesis and potential therapeutic targets.
Insights
Aristolochic acids (AA) are linked to liver cancer (HCC). This study identifies PSMB4 as a key gene connecting AA exposure to HCC development, suggesting it as a potential therapeutic target.
Area of Science:
- Toxicology
- Oncology
- Bioinformatics
Background:
- Aristolochic acids (AA) are natural carcinogens in herbal medicines.
- Hepatocellular carcinoma (HCC) is a major liver cancer.
- The molecular link between AA and HCC remains unclear.
Purpose of the Study:
- Investigate the molecular mechanisms of AA-induced liver cancer.
- Identify key molecular targets in AA-driven hepatocarcinogenesis.
- Explore potential therapeutic strategies for AA-related HCC.
Main Methods:
- Integrated toxicogenomic and HCC gene datasets.
- Constructed protein-protein interaction networks.
- Applied machine learning for gene prioritization.
- Validated findings using bioinformatics, molecular docking, and simulations.
Main Results:
- Identified 2378 overlapping genes between AA and HCC.
- Highlighted activated proteasome, cell cycle, and antigen processing pathways.
- Prioritized PSMB4 as a core gene overexpressed in HCC, linked to poor prognosis and immune infiltration.
- Confirmed stable binding between AA and PSMB4.
Conclusions:
- Established a mechanistic link between AA and HCC via network toxicology and machine learning.
- Identified PSMB4 as a potential biomarker and therapeutic target.
- Provided insights into toxicant-driven liver cancer development.
