Complement and coagulation cascade cross-talk in endometriosis and the potential of Janus Kinase inhibitors-a network
Monika Golinska1,2, Aleksander Rycerz1, Matylda Sobczak1
1Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
Background:
Molecular events that drive endometriosis (EM) and cause accompanying immune deregulation remain elusive. Our purpose was to identify key pathways involved in lesion formation across diverse populations and to detect transcriptomic changes in eutopic endometrium that accompany EM.
Methods:
We searched Gene Expression Omnibus and ArrayExpress and performed differential gene expression analysis and a network meta-analysis on nine qualifying datasets. Those contained transcriptomic data on 114 ectopic endometrium samples (EL), 138 eutopic endometrium samples from women with endometriosis (EEM), and 79 eutopic endometrium samples from women without endometriosis (EH). Gene ontology and enrichment analysis were performed in DAVID, Metascape, and Cytoscape, and drug repurposing was done in CMap.
Results:
EEM compared to EH upregulated CCL21 and downregulated BIRC3, CEL, and LEFTY1 genes (|log2FC| > 0.5, p < 0.05). EL showed increased expression of complement and serpin genes (EL vs. EEM: C7, logFC = 3.38, p < 0.0001; C3, logFC = 2.40, p < 0.0001; SERPINE1, logFC = 1.02, p < 0.05; SERPINE2, logFC = 1.54, p < 0.001) and mast cell markers (EL vs. EEM: CPA3, logFC = 1.54, p < 0.0001; KIT, logFC = 0.74, p < 0.001). Functional enrichment analysis highlighted complement and coagulation, inflammation, angiogenesis, and extracellular matrix remodeling as drivers of endometriosis. Pharmacogenomic analysis indicated Janus kinase (JAK), cyclin-dependent kinase (CDK), and topoisomerase inhibitors as therapy targets.
Conclusion:
Our results suggest an interplay between complement and coagulation, mast cells, extracellular matrix remodeling, and the JAK/STAT3 pathway in endometriosis. We underscore the significance of complement C3 and propose JAK inhibitors as therapy candidates. Detected expression differences between EEM and EH are important for the development of diagnosis via endometrial biopsy.
Insights
Endometriosis involves immune deregulation, complement, and coagulation pathways. Complement C3 and JAK inhibitors show therapeutic potential for this condition.
Area of Science:
- Reproductive Biology
- Immunology
- Genomics
Background:
- Endometriosis (EM) pathogenesis and immune dysregulation mechanisms are not fully understood.
- Identifying key molecular pathways in EM lesion formation and associated transcriptomic changes in eutopic endometrium is crucial.
Purpose of the Study:
- To identify key molecular pathways driving endometriosis lesion formation.
- To detect transcriptomic alterations in eutopic endometrium associated with endometriosis.
- To explore potential therapeutic targets for endometriosis.
Main Methods:
- Utilized Gene Expression Omnibus and ArrayExpress for transcriptomic data.
- Performed differential gene expression and network meta-analysis on samples from women with and without endometriosis.
- Conducted gene ontology, enrichment, and pharmacogenomic analyses.
Main Results:
- Identified differential gene expression in eutopic endometrium (e.g., CCL21, BIRC3, CEL, LEFTY1).
- Ectopic lesions showed increased expression of complement (C7, C3) and mast cell markers (CPA3, KIT).
- Highlighted complement/coagulation, inflammation, angiogenesis, and ECM remodeling as key drivers; identified JAK, CDK, and topoisomerase inhibitors as potential targets.
Conclusions:
- Endometriosis involves an interplay of complement/coagulation, mast cells, ECM remodeling, and JAK/STAT3 signaling.
- Complement C3 and JAK inhibitors are significant therapeutic candidates.
- Transcriptomic differences between eutopic endometrium in women with and without endometriosis may aid diagnostic development.
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