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Published on: May 16, 2016
Integrating TWAS, chemical-genomic networks, and experimental models: melatonin as a ferroptosis inhibitor in
Ruoyang Feng1, Yirixiati Aihaiti2,3, Hui Yu2,3
1Department of Orthopedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Background:
Osteoarthritis (OA) is a degenerative joint disease with limited therapeutic options, and its molecular mechanisms remain poorly understood.
Methods:
We employed a multi-faceted approach combining transcriptome-wide association studies (TWAS), chemical-genomic enrichment analysis (CGSEA), and network pharmacology to identify OA-related chemicals and construct a disease-drug interaction network. Molecular docking was performed to assess melatonin's binding affinity to ferroptosis-related proteins. Melatonin was selected as a candidate for further investigation. In vitro experiments were conducted using SW1353 chondrocytes to validate the effects of melatonin on IL-1β-induced ferroptosis, extracellular matrix degradation, and inflammatory responses.
Results:
Molecular docking confirmed melatonin's strong binding affinity to ferroptosis-related proteins. In vitro experiments with IL-1β-stimulated SW1353 chondrocytes revealed that melatonin reversed IL-1β-induced ferroptosis by restoring SLC7A11/GPX4 expression, reducing ROS accumulation, and suppressing P53 activation. Melatonin also mitigated extracellular matrix degradation (via COL2A1/MMP13 modulation) and inflammatory responses (via COX-2/iNOS downregulation).
Conclusion:
These findings demonstrate that melatonin alleviates OA progression by inhibiting ferroptosis and inflammation, offering a novel therapeutic strategy. This study integrates computational and experimental validation to elucidate melatonin's mechanism in OA, supporting its clinical potential. Key points • Identification of melatonin as a potential therapeutic agent for osteoarthritis (OA) by TWAS, CGSEA, and network pharmacology conjoint analysis. • Molecular docking shows strong binding capacity of melatonin to iron death-related proteins (e.g., GPX4, SLC7A11). • Experimentally confirmed that melatonin significantly reversed IL-1β-induced iron death in chondrocytes by restoring SLC7A11/GPX4 expression, inhibiting P53 activation and reducing ROS accumulation.
Insights
Melatonin shows promise for osteoarthritis (OA) treatment by inhibiting ferroptosis and inflammation. This study used computational and experimental methods to confirm melatonin
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology
- Genetics
Background:
- Osteoarthritis (OA) is a degenerative joint disease with limited therapeutic options.
- The molecular mechanisms underlying OA pathogenesis are not fully understood.
- Current OA treatments lack efficacy and target specific pathways.
Purpose of the Study:
- To identify potential therapeutic agents for OA using computational approaches.
- To investigate the therapeutic potential of melatonin in OA.
- To elucidate the molecular mechanisms of melatonin action in OA.
Main Methods:
- Transcriptome-wide association studies (TWAS), chemical-genomic enrichment analysis (CGSEA), and network pharmacology were employed.
- Molecular docking was used to assess melatonin's binding affinity to ferroptosis-related proteins.
- In vitro experiments using SW1353 chondrocytes validated melatonin's effects on IL-1β-induced ferroptosis, extracellular matrix degradation, and inflammation.
Main Results:
- Melatonin demonstrated strong binding affinity to ferroptosis-related proteins (e.g., GPX4, SLC7A11).
- Melatonin reversed IL-1β-induced ferroptosis in chondrocytes by restoring SLC7A11/GPX4 expression, reducing ROS, and inhibiting P53 activation.
- Melatonin mitigated extracellular matrix degradation and inflammatory responses in chondrocytes.
Conclusions:
- Melatonin alleviates OA progression by inhibiting ferroptosis and inflammation, presenting a novel therapeutic strategy.
- This study integrates computational and experimental validation to support melatonin's clinical potential in OA.
- Melatonin's mechanism involves restoring ferroptosis-related gene expression and modulating inflammatory pathways.
