Clinical rheumatology · 2025
Integrating TWAS, chemical-genomic networks, and experimental models: melatonin as a ferroptosis inhibitor in osteoarthritis therapy.
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Feng Ruoyang, Aihaiti Yirixiati, Yu Hui, Xu Ke, Lu Chao, Xu Peng
Аннотация
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.
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.