Complement and coagulation cascade cross-talk in endometriosis and the potential of Janus Kinase inhibitors—a network meta-analysis

Monika Golinska, Aleksander Rycerz, Maria Sobczak, Matylda Sobczak, Jędrzej Chrzanowski, Jedrzej Chrzanowski, Konrad Stawiski, Wojciech Fendler
Frontiers in immunology · 2025 · vol. 16 , pp. 1619434 · doi:10.3389/fimmu.2025.1619434 · PMID:40698088 · PMC12279843 · W4412100386
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This network meta-analysis identified complement and coagulation cascade cross-talk, mast cell involvement, and extracellular matrix remodeling as drivers of endometriosis, with Janus kinase inhibitors proposed as potential therapeutic targets.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This study systematically searched GEO and ArrayExpress for bulk transcriptomic studies of ectopic endometrium (EL), eutopic endometrium from women with endometriosis (EEM), and eutopic endometrium from women without endometriosis (EH), then performed differential expression and a network meta-analysis across nine datasets (114 EL, 138 EEM, 79 EH). Key findings were that EEM vs EH upregulated CCL21 and downregulated BIRC3, CEL, and LEFTY1, while EL vs EEM showed increased complement and serpin genes (e.g., C7, C3, SERPINE1/2) and mast cell markers (e.g., CPA3, KIT); enrichment analyses highlighted complement/coagulation, inflammation, angiogenesis, and extracellular matrix remodeling, and pharmacogenomic mapping pointed to JAK/STAT3-related targets among others. A major caveat is that the authors describe the differential expression stage as exploratory without multiple-testing correction, relying on consistency across datasets and later pathway/drug analyses with appropriate corrections. This paper is centrally about endometriosis—network meta-analysis of transcriptomic changes pointing to complement/coagulation cross-talk and the JAK/STAT3 pathway, with discussion of JAK inhibitors and biopsy-relevant gene differences.

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Abstract

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 (|log 2 FC| > 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.

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Condition tags

endometriosis

MeSH descriptors

Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation Blood Coagulation

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