Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol
Siming Dai1, Hui Wang1, Meng Wang2
1Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China.
Introduction:
Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism.
Method:
Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies.
Results:
In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA.
Conclusion:
This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA. Key Points • Our study provides a strong indication that further study of celastrol therapy in OA is required. • mTOR is the most likely therapeutic target of celastrol in OA.
Insights
Celastrol shows potential for osteoarthritis (OA) treatment by targeting the mTOR pathway. This study identified 96 celastrol targets and confirmed mTOR as the most likely therapeutic target for OA.
Area of Science:
- Pharmacology
- Molecular Biology
- Computational Biology
Background:
- Celastrol is a potential therapeutic agent for osteoarthritis (OA).
- The precise mechanism of celastrol's action in OA remains unclear.
- This study aimed to elucidate celastrol's function and mechanism in OA.
Purpose of the Study:
- To identify celastrol's potential targets and functions in osteoarthritis.
- To determine the underlying molecular mechanism of celastrol in OA treatment.
- To validate predicted targets through computational and simulation methods.
Main Methods:
- Collected celastrol and OA targets from databases and literature.
- Performed transcriptomics sequencing and identified overlapping genes.
- Utilized Gene Ontology (GO) and KEGG pathway analysis for functional enrichment.
- Constructed a celastrol-target network and validated predictions via molecular docking and dynamics simulations.
Main Results:
- Identified 96 putative celastrol targets involved in OA pathogenesis.
- Observed involvement in cellular responses, apoptosis, and aging.
- Highlighted the mTOR and AGE-RAGE signaling pathways.
- Pinpointed 13 core targets, with mTOR identified as the most probable therapeutic target.
Conclusions:
- Provides novel insights into celastrol's mechanism against OA.
- Suggests further investigation into celastrol therapy for OA is warranted.
- Establishes mTOR as the primary therapeutic target for celastrol in OA treatment.
