{"paper_id":"20834916-a2be-464b-b84a-c1f2097f3017","body_text":"1 \n \nTitle: 1 \nComplement and coagulation cascade cross-talk in endometriosis and the potential of 2 \nJAK inhibitors – a network meta-analysis. 3 \n 4 \nMonika Golinska1,, Aleksander Rycerz1, Matylda Sobczak1, Jedrzej Chrzanowski1, Konrad 5 \nStawiski1, Wojciech Fendler1,2 6 \nAffiliations: 7 \n1 - Department of Biostatistics and Translational Medicine, Medical University of Lodz, 8 \nLodz, Poland 9 \n2 - Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 10 \n 11 \nCorresponding Author: 12 \nMonika Golinska, Department of Biostatistics and Translational Medicine 13 \nMedical University of Lodz, Poland, 15 Mazowiecka St., 92-215 Lodz 14 \n+48 42 272 25 85, monika.golinska@umed.lodz.pl 15 \n 16 \n 17 \n 18 \n 19 \n 20 \n 21 \n 22 \n 23 \n 24 \n 25 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \nAbstract  26 \nBackground 27 \nLack of knowledge on the processes driving endometriosis hinders early detection and 28 \ntherapy development. Our purpose was to identify key molecular events involved in lesion 29 \nformation across diverse populations and to detect transcriptomic changes in eutopic 30 \nendometrium that accompany endometriosis. 31 \nMethods 32 \nWe searched Gene Expression Omnibus and ArrayExpress and performed differential gene 33 \nexpression analysis and a network meta-analysis on nine qualifying datasets. Those contained 34 \ntranscriptomic data on: 114 ectopic endometrium samples (EL), 138 eutopic endometrium 35 \nsamples from women with endometriosis (EEM) and 79 eutopic endometrium samples from 36 \nwomen without endometriosis (EH). Gene ontology and enrichment analysis was performed 37 \nin DA VID, Metascape and Cytoscape and drug repurposing was done in CMap. 38 \nResults 39 \nEEM compared to EH upregulated CCL21 and downregulated BIRC3, CEL and LEFTY1 40 \ngenes (|log2FC|>0.5, p<0.05). EL showed increased expression of complement and serpin 41 \ngenes (EL vs EEM: C7, logFC = 3.38, p <0.0001; C3, logFC = 2.40, p<0.0001; SERPINE1, 42 \nlogFC = 1.02; p<0.05; SERPINE2, logFC = 1.54, p<0.001) and mast cells markers (EL vs 43 \nEEM: CPA3, logFC = 1.54, p<0.0001, KIT, logFC=0.74, p<0.001). Functional enrichment 44 \nanalysis highlighted complement and coagulation, inflammation, angiogenesis and ECM as 45 \ndrivers of endometriosis. Pharmacogenomic analysis indicated JAK, CDK and topoisomerase 46 \ninhibitors as therapy targets.  47 \nConclusion 48 \nOur results suggest an interplay between complement and coagulation, mast cells, ECM and 49 \nJAK/STAT3 pathway in endometriosis. We underscore the significance of complement C3 50 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n3 \n \nand propose JAK inhibitors as therapy candidates. Detected expression differences between 51 \nEEM and EH are important for the development of diagnosis via endometrial biopsy. 52 \n 53 \nKeywords: endometriosis, eutopic and ectopic endometrium, network meta-analysis, 54 \ncomplement and coagulation, mast cells, JAK inhibitors 55 \n 56 \nAbbreviations: endometriosis (EM), endometrium from healthy controls (EH), endometrium 57 \nfrom women with endometriosis (EEM), endometrial lesions (EL), differentially expressed 58 \ngenes (DEGs), Gene Expression Omnibus (GEO) 59 \n 60 \nWHAT IS ALREADY KNOWN ON THIS TOPIC 61 \n• Pathways and genes involved in endometriosis lesions formation are not well 62 \ncharacterised. Studies encompassing diverse patients populations are missing. 63 \nWHAT THIS STUDY ADDS 64 \n• This study reveals the transcriptomic profile of endometriosis, obtained via integration 65 \nof nine different datasets spanning various ethnicities and demographics. It 66 \ndemonstrates the importance of complement and coagulation cascades, mast cells and 67 \nJAK/STAT3 pathway in lesion development. Our meta-analysis identifies 68 \ntranscriptomic differences in eutopic endometrium of women with and without 69 \nendometriosis which include changes in CCL21, BIRC3, CEL and LEFTY1 70 \nexpression. 71 \nHOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY 72 \n• Our comprehensive analysis of endometriosis transcriptomic profile highlights genes 73 \nand pathways that should be explored further as disease biomarkers. JAK inhibitors 74 \ncurrently used in clinic in other autoimmune diseases show treatment potential. Gene 75 \nexpression differences between eutopic endometrium of women with and without 76 \nendometriosis should be further explored as biomarkers in endometrial biopsy. 77 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n4 \n \nINTRODUCTION 78 \nLack of knowledge on the key processes that drive endometriosis hinders its early detection 79 \nand therapy development. There is a need to define those molecular events and to understand 80 \nhow they interact to foster lesion implantation and maintenance. 81 \nEndometriosis is a chronic and complex disease currently showing a median diagnostic delay 82 \nof 7- 9 years 1,2. There has been a significant progress in the development of endometriosis 83 \nimaging protocols3, however, laparoscopy remains a gold standard for final diagnosis. There 84 \nis a need to explore the less invasive endometrial biopsy option. To consider this strategy, the 85 \nin-depth knowledge on the molecular differences in eutopic endometrium of healthy controls 86 \nand women with endometriosis is needed.  87 \nSeveral attempts have been made at delineating disease biomarkers, but to date this has not 88 \nyet proven successful. Various omics technologies enabled identification of key genes related 89 \nto the pathophysiology of endometriosis. However, a consensus has not yet been reached, and 90 \nwe are still missing the focal points on which to concentrate the therapeutic endeavors. A 91 \nmulti-cohort analysis is needed to address the issue in an unbiased and comprehensive 92 \nmanner. 93 \nIn this article we aimed to better understand complex events that underlie endometriotic 94 \nlesion formation and progression. To achieve this, we systematically reviewed endometriosis 95 \ndata and performed network meta-analysis on chosen datasets. We generated a transcriptomic 96 \nprofile of endometriosis, determined the key pathways involved in lesion formation and 97 \nexplored possible drug candidates for endometriosis therapy. 98 \n 99 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n5 \n \nMETHODS 100 \nSearch strategy and study selection 101 \nGene Expression Omnibus (GEO) and ArrayExpress were searched using terms 102 \n“endometriosis” and “Homo sapiens” and filtered with terms \"Expression profiling by array\" 103 \nor \"Expression profiling by high throughput sequencing\". MEDLINE/Pubmed was searched 104 \nfor publications that correspond to those publicly deposited datasets.  105 \n 106 \nStudies included in the analysis had to contain at least two tissues of interest: ectopic 107 \nendometrium - endometrial lesion (EL), eutopic endometrium from women without 108 \nendometriosis (EH) or eutopic endometrium from women with endometriosis (EEM).  109 \nInclusion criteria were predefined and stringent to minimize the risk of bias, focusing on 110 \ndatasets using RNA-Seq or microarray technologies, with available raw data. Transcriptomic 111 \nanalysis had to be performed directly on human endometrial tissue, that had not been 112 \nsubjected to any manipulation or cell isolation prior to RNA extraction. Samples had to be 113 \ntaken from patients not on hormonal treatment in three months preceding tissue collection. 114 \nThe presence or absence of endometriosis had to be confirmed with laparoscopy for samples 115 \nto be included in our study. Only datasets with accompanying publication were considered to 116 \nensure all information about samples was available. Datasets with incomplete information 117 \nwere excluded to reduce variability and minimize errors. A full list of inclusion / exclusion 118 \ncriteria together with the PRISMA selection flowchart are summarized in Table S1 and Fig. 1. 119 \nTwo independent reviewers screened datasets for relevance, and any discrepancies were 120 \nresolved in discussion with a third reviewer. PRISMA guidelines were followed, and study 121 \nprotocol was registered in PROSPERO (ID CRD42024548098).   122 \n 123 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n6 \n \nData extraction and Differential Gene Expression 124 \nEach dataset was analyzed individually to ensure that data-specific preprocessing and 125 \nnormalization steps were applied appropriately. For microarray datasets, the raw data files 126 \nwere retrieved from the GEO repository using the R package “GEOquery”. The 127 \npreprocessing of microarray data was conducted following the manufacturer's protocols. 128 \nBackground correction and quantile normalization were applied for all array data. To adjust 129 \nfor differences in library size and transcript length, the raw reads count from RNA-Seq 130 \ndatasets were normalized and scaled using the average transcript length for each sample. 131 \nFollowing this, library size normalization was performed using the Trimmed Mean of M-132 \nvalues (TMM). After preprocessing, group comparisons were conducted on the normalized 133 \ndatasets to identify differentially expressed genes (DEGs) between experimental groups. For 134 \nthis purpose, the “limma” package in R was utilized. The analysis generated log fold change 135 \n(logFC) values and their corresponding standard error (SE) values which were used for 136 \nfurther analysis. 137 \n 138 \nNetwork meta-analysis 139 \nNetwork meta-analysis on gene expression was performed using “netmeta” package. 140 \nAlthough meta-analysis allows for the determination of both direct and indirect effects, in our 141 \nsubsequent analyses, we focused on the combined effect to maximize the quality of the 142 \nanalyzed data and reduce the influence of less reliable direct or indirect effects. For 143 \ninvestigated difference measurement we used logFC and its corresponding standard error. 144 \nThese were interpreted as the mean difference and the standard error of the mean difference, 145 \nrespectively, which are widely used metrics in comparative gene expression studies. This 146 \nstandardization ensures that the results are both interpretable and comparable across datasets.  147 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n7 \n \nWe performed 7664 network meta-analysis for genes that occurred in each of datasets 148 \nincluded in the study. Genes with a p-value < 0.05 were considered statistically significant 149 \nand a |logFC|>0.5 was used to filter genes with biologically meaningful changes in 150 \nexpression.  151 \nRisk of bias 152 \nTo reduce the risk of bias, we included studies with raw data deposited and results published 153 \nin peer-review journals. Information from accompanying publication was used to ascertain 154 \nthe quality of the study and to identify if the absence of endometriosis was properly 155 \ndetermined and to confirm that tissue did not undergo any manipulation prior to RNA 156 \nisolation. 157 \nHeterogeneity was evaluated using I² statistics and Cochran’s Q-test, while sensitivity 158 \nanalyses validated the robustness of findings. Funnel plots were generated to assess bias. 159 \nThese measures ensured a thorough evaluation of potential biases, enhancing the reliability 160 \nand validity of the meta-analytic findings. 161 \n 162 \nGene ontology and pathway analysis  163 \nThe list of DEGs obtained from the network meta-analysis was submitted to DA VID for gene 164 \nontology and KEGG and Reactome pathways analysis. For functional clustering, we applied 165 \na cut-off enrichment score of >2.5, p<0.05 and medium classification stringency. The same 166 \nlist of DEGs was analyzed in Metascape v3.5.2024.0101 and the most enriched terms were 167 \nvisualized in Cytoscape v3.10.2. 168 \n 169 \nComputational pharmacogenomics 170 \nTo identify pharmacological compounds likely to reverse endometriosis gene signature, we 171 \nqueried drug repurposing reference database - CMap. We submitted a list of 150 up- and 150 172 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n8 \n \ndown-regulated genes that had the highest combined logFC for EL vs EH and EL vs EEM 173 \ncomparisons and p<0.05.  174 \n 175 \n 176 \n 177 \nRESULTS 178 \nCharacteristics of chosen studies 179 \nNine datasets met the inclusion criteria (Fig. 1 and Table S1) and were included in the 180 \nanalysis (Table 1). Those contained transcriptomic data on 114 ectopic endometrium samples 181 \n(EL), 138 eutopic endometrium samples from women with endometriosis (EEM) and 79 182 \neutopic endometrium samples from women without endometriosis (EH). The absence of 183 \nendometriosis in the healthy (EH) group had to be confirmed during laparoscopic procedure. 184 \nTissues were collected at three different continents and encompassed all types and stages of 185 \nendometriosis (clinical data in Table S2).  186 \n 187 \nGEO \nAccession \nNumber \nMethod \nNumber \nof \ndetected \ngenes \nEctopic \nendometrium \n(EL, n=114) \nEutopic \nendometrium \nfrom \npatients with \nendometriosis \n(EEM, \nn=138) \nEutopic \nendometrium \nfrom patients \nwithout \nendometriosis/ \nhealthy \ncontrol \n(EH, n=79) \nGSE2327134 \nhigh \nthroughput \nsequencing \n17488 - 7 7 \nGSE153740 \n& \nGSE1537395 \nhigh \nthroughput \nsequencing \n16840 \n& \n17449 \n- 4 & 4 4 & 3 \nGSE1415496 microarrays 19746 79 49 21 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n9 \n \nGSE1340567 \nhigh \nthroughput \nsequencing \n18885 - 16 22 \nGSE256288 microarrays 12644 7 9 6 \nGSE378379 microarrays 21094 18 18 - \nGSE636410 microarrays 20857 - 21 16 \nGSE730511 microarrays 20857 10 10 - \n 188 \nTable 1. Characteristics of GEO datasets chosen for the network meta-analysis. 189 \nReferences next to each dataset identifier refer to the original publication.   190 \n 191 \n 192 \nTranscriptomic profile of eutopic and ectopic endometrium. 193 \nDifferential expression analysis was performed for each of the three comparisons: EL vs 194 \nEEM, EL vs EH and EEM vs EH. Using p <0.05 and |logFC|>0.5, we identified 1109 DEGs 195 \nbetween EL and EEM, 1267 DEGs between EL and EH and 4 DEGs between EEM and EH 196 \n(Fig. 2). The heatmap of top 40 up and down regulated genes for all comparisons per dataset 197 \nis presented in Fig. 2D. The full list of network meta-analysis results is deposited in 198 \nSupplementary Dataset S1. 199 \nMeta-analysis revealed that transcriptomic profile of lesions was profoundly different from 200 \nthat of eutopic endometrium (Fig. 2A-B) while the eutopic endometrium from women with 201 \n(EEM) and without endometriosis (EH) differed in the expression of four genes only (Fig. 202 \n2C). BIRC3, CEL and LEFTY1  were significantly less expressed in endometrium of women 203 \nwith endometriosis than without (logFC = -0.79, p = 0.0051; logFC = -0.52, p = 0.0051; 204 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n10 \n \nlogFC = -0.61, p = 0.0099, respectively). CCL21  was significantly higher in EEM versus EH 205 \n(logFC=0.59, p = 0.0255) and even higher when EL with EEM was contrasted (logFC=1.57, 206 \np < 0.0001, Fig. 2C). C-C motif chemokine ligand 21 ( CCL21) is an inflammatory mediator 207 \nassociated with moderate to severe endometriosis 12, however to-date its use as a disease 208 \nbiomarker has failed. Our results showed a directional increase of CCL21  from endometrium 209 \nof healthy patients through that of endometriosis sufferers to lesions themselves indicating its 210 \nrole in the eutopic endometrium inflammation in patients with endometriosis. 211 \n 212 \nPathways contributing to lesion development 213 \nIn further analysis, we selected genes that showed differential expression in both EL vs. EEM 214 \nand EL vs. EH comparisons (the intersection of the sets, Fig. 2E) and exhibited the same 215 \ndirection of expression. For p<0.05 and |logFC|>0.5 we obtained a list of 989 DEGs: 536 216 \nupregulated and 453 downregulated, on which we performed functional annotation and 217 \nenrichment analyses (Fig. 3A and detailed in Table S3A). Results presented below satisfied a 218 \np value below 0.0001. Those analyses revealed that most biological processes involved in the 219 \nformation of endometriotic lesions were linked to cell adhesion (6.6%), inflammatory 220 \nresponse (5.5%) and regulation of angiogenesis (2.9%). The gene ontology molecular 221 \nfunctions analysis showed that the DEGs were significantly enriched in protein binding 222 \n(76.7%), identical protein binding (15%) and extracellular matrix structural constituent 223 \n(2.5%). In the cellular component, DEGs were mainly involved in extracellular exosome 224 \n(21.2%), extracellular region (21.2%) and extracellular space (17.4%).  225 \nKEGG analysis showed enrichment in complement and coagulation cascades (2.5%), 226 \nStaphylococcus aureus infection (2.3%) and cell adhesion molecules (2.7%). The analysis 227 \nagainst Reactome database revealed a key role of extracellular matrix organization (5.2%), 228 \nregulation of complement cascade (1.5%) and complement cascade (1.6%) (Table S3B).  229 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n11 \n \nA further pathway enrichment analysis was performed with Metascape (Fig. 3B and Table 230 \nS4) and visualized in Cytoscape (Fig. 3C). Tube morphogenesis, which relates to vascular 231 \ndevelopment, was the highest ranked result of enrichment analysis (Fig. 3B). Inflammatory 232 \nand hormonal response as well as locomotion and proliferation were amongst the top 10 most 233 \nenriched pathways with count value above 75. Functional annotation clustering revealed that 234 \nthe complement cascade was the most enriched with the score of 4.14, followed by platelet 235 \nactivation pathways, DNA remodeling and regulation of transcription and cell/cell-matrix 236 \nadhesion processes (enrichment score of 3.77, 3.02 and 2.71 respectively (Fig. 3D). 237 \n 238 \nAltered expression of complement and coagulation pathway genes. 239 \nComplement and coagulation cascade was the most enriched KEGG pathway for the ectopic 240 \nversus eutopic endometrium comparison (Fig. 3D). Genes including C3, C2, C3 and SERPIN 241 \nsuperfamily genes involved in this pathway were amongst the most differentially expressed in 242 \nendometrial tissue (Fig. 4 and Dataset S1).  243 \nComplement genes C1QA (logFC = 1.12; 95%CI = 0.77, 1.47), C3 (logFC = 2.40; 95%CI = 244 \n1.43, 3.37) and C7 (logFC = 3.36; 95%CI = 2.50, 4.26) were upregulated in endometrial 245 \nlesions and showed high logFC values (Fig. 4A-C). C7 was the gene that showed the highest 246 \nlevel of upregulation among all examined genes.  247 \nSerpins regulate coagulation fibrinolysis processes13 and were implicated in the development 248 \nof endometriosis 14–16. Our network meta-analysis showed that serpin genes were 249 \ndifferentially expressed between endometrial lesions and eutopic endometrium. In 250 \ncomparison with the above presented complement genes, serpin family genes were 251 \ncharacterized by more heterogenous expression between investigated datasets. SERPINE1 252 \nand SERPINE2 were upregulated (logFC = 1.02; 95%CI = 0.15, 1.90 and logFC = 1.54; 253 \n95%CI = 0.80, 2.27 respectively) while SERPINA5 was downregulated in lesions (logFC = -254 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n12 \n \n0.85; 95%CI = -1.52, -0.16, Fig. 4D-F). Detailed comparisons for each of the subgroups can 255 \nbe found in Dataset S1.  256 \n 257 \nMast cells markers 258 \nOur data showed an upregulation in the expression of mast cells markers including CP A3 259 \n(logFC = 1.54; 95%CI = 0.96, 2.11), KIT (logFC = 0.74; 95%CI = 0.30, 1.18), MS4A6A 260 \n(logFC = 0.71; 95%CI = 0.30, 1.11) and markers of mast cells activation FCGR2B (logFC = 261 \n0.78; 95%CI = 0.20, 1.35) and S100A10 (logFC = 0.87; 95%CI = 0.38, 1.35, Fig. S3A-E). 262 \nThe expression of MS4A4A and MS4A2  was also higher in lesions (Dataset S1). Higher 263 \namounts of mast cells and their increased degranulation have been reported in endometrial 264 \ntissue of animal models and humans 17,18; mast cells colocalized to the vasculature of ovarian 265 \nendometriomas and they were found to promote endometrial cells migration in in vitro 266 \nassays19.  267 \n 268 \nRepurposing JAK and CDK inhibitors for endometriosis therapy. 269 \nWe used CMap drug repurposing software to find most probable connections between 270 \ntherapeutic drugs and our network meta-analysis results. A median tau score value of 90 or 271 \nabove is considered the typical threshold for assessing meaningful drug-induced effects. We 272 \napplied a median tau score cutoff at 95 and selected the top 15 hits. This analysis indicated 273 \nthat the candidates most likely to reverse the endometriosis mRNA profile were cyclin-274 \ndependent kinase (CDK) inhibitors, JAK and topoisomerase inhibitors (Fig. 3E).  275 \nJAK/STAT3 pathway is thought to govern migratory and invasive properties of cells. Its 276 \nprolonged activation in breast cancer was linked with tumor development and resistance to 277 \ntaxane and platinum therapy 20. Our results showed an increase in the expression of STAT5A 278 \n(logFC = 0.83; 95%CI = 0.57, 1.08) and STAT5B (logFC = 0.57; 95%CI = 0.37, 0.77) in 279 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n13 \n \nlesions compared with control tissue (Fig. S3 G-H). JAK3 significantly increased as well but 280 \nlogFC value was below 0.5 (Dataset S1).  281 \nJAK inhibitor Ruxolitinib reduced epithelial ovarian cancer cell viability and caused growth 282 \ninhibition of Tam resistant breast cancer cells in vitro. It was shown to lower mRNA VEGF 283 \nexpression and reduce the number of vessels and overall tumor weight in chorioallantoic 284 \nassay20. Ruxotinilib is currently tested in combination therapy for endometrial cancer but its 285 \nuse in vitro or in preclinical models of endometriosis has not been reported. Tofacitinib, 286 \nanother JAK inhibitor, showed a decrease in endometrial lesion size in mice and reduced 287 \nproliferation of endometrial cancer cells in vitro21.  288 \n 289 \nDISCUSSION 290 \nUnderstanding the main pathways involved in endometriosis development is necessary for 291 \nthe successful biomarker discovery and improved therapy outcomes. Combining data in 292 \nmeta-analysis, we highlight pathogenetic mechanisms that are critical for lesion formation 293 \nregardless of endometriosis subtypes and patients’ characteristics.  294 \n 295 \nEndometrium of women with endometriosis differs from healthy controls 296 \nWe detected differences in gene expression between endometrium of healthy women and 297 \nthose suffering from endometriosis thus showing that endometriosis can also affect eutopic 298 \nendometrium (Fig. 2C). CCL21  was upregulated whilst BIRC3 , LEFTY1 and CEL were 299 \ndownregulated in EEM versus EH. Increased expression of CCL21 could suggest that this 300 \ngene takes part in inducing early inflammatory changes in eutopic endometrium in women 301 \nwith endometriosis and that it continues its role in established lesions (Dataset S1). 302 \nBaculoviral IAP repeat containing 3 ( BIRC3) has not been studied in the context of 303 \nendometriosis. However, its mutations are often present in endometroid adenocarcinoma and 304 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n14 \n \nendometrial cancer 22. In the latter, the lower protein levels of Birc3 correlate with worse 305 \npatient survival. One could speculate that the decreased B irc3 expression in EEM could 306 \ncontribute to the transformation of endometrium into lesions. Endometrial bleeding 307 \nassociated factor (EBAF/ LEFTY1) partakes in the regulation of cyclical exfoliation of 308 \nendometrium and in decidualization. Healthy endometrium does not express LEFTY1 during 309 \nimplantation window while endometrium of women suffering from endometriosis as well as 310 \ninfertility showed its expression 23. Our results agree with that finding and suggest that the 311 \nhigher LEFTY1 expression in EEM group could contribute to endometriosis-related 312 \ninfertility. CEL gene encodes carboxyl ester lipase, which partakes in cholesterol and lipid-313 \nsoluble vitamin ester hydrolysis. Its role so far is implicated in diabetes and hereditary 314 \npancreatitis and progression of atherosclerosis. The CEL gene has not yet been studied in the 315 \ncontext of endometriosis. 316 \n 317 \nThe complement and coagulation cascade in lesion formation. 318 \nWe further focused on delineating the expression profile that can differentiate ectopic 319 \nendometrium from eutopic endometrium from women with and without endometriosis (Fig. 320 \n2). Gene ontology analyses highlighted crucial events accompanying lesion formation. Those 321 \nwere immune system activation, angiogenesis, regulation of transcription, response to 322 \nhormones and cytokines, cell adhesion and ECM – cell surface interactions (Fig. 3). The 323 \nimportance of immune system deregulation in endometriosis has been reported previously; 324 \nvarious inflammatory phenotypes have been associated with increased risk of 325 \nendometriosis24,25. Our result showed that the complement system and platelet coagulation 326 \nare the two most enriched pathways in endometriosis (Fig. 3D). Both processes are essential 327 \nin natural endometrium growth and shedding cycle. The fact that both pathways are the most 328 \nenriched agrees with the current theory that women prone to endometriosis are likely to have 329 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n15 \n \na different, dysregulated peritoneal microenvironment. The complement system is a mediator 330 \nof tissue growth and regeneration and its activation has for a long time been implicated in the 331 \ndevelopment of autoimmune disease and in promoting tumor growth. Its dysregulation could 332 \ntherefore provide means for immunosurveillance escape and facilitate the implantation of 333 \nlesions. Its importance in the development of endometriosis has been suspected since the 334 \n80’s26 and confirmed more recently 27,28. Higher amounts of C1, C3 and C5 have been 335 \ndetected in serum 29 and peritoneal fluid of women with endometriosis 30,31. V arious 336 \ncomplement proteins were shown to be present in epithelial cells of endometrial lesions and 337 \novarian cancer tumors. Its local synthesis and deposition has been correlated with progression 338 \nof various cancer types. 339 \nOur data revealed an increased mRNA expression of C1q, C2, C6 but especially C3 and C7 in 340 \nthe lesions (Fig. 4A-C, Dataset S1). C7, a complement cascade member responsible for 341 \ninitiation of membrane attack complex, was the most overexpressed gene with the highest 342 \nfold change in our comparison between diseased and control tissue suggesting its significant 343 \nrole in lesion formation (Fig. 2A-B, Fig. 4C). C7 was found to contribute to inflammation 344 \nand tissue damage in endometriosis32; it has previously been shown overexpressed in ovarian 345 \ncancer25 and stromal cells of endometriomas33. 346 \nC3, a major effector, at which all complement pathways converge, was one of the most 347 \ndifferentially expressed genes in endometriosis (Fig. 4B, Figure S2). C3 dysregulation is 348 \ninvolved in most if not all inflammatory diseases; it has been found upregulated in cancer, 349 \ncardiac and neurological diseases, asthma and obesity. Patients with inflammatory bowel 350 \ndisease had a higher expression of C3 in their intestinal tissue and this was thought to 351 \ncontribute to chronic inflammation and tissue injury. A similar situation could occur in 352 \nendometriosis; increased C3 expression could contribute to inflammation-driven peritoneal 353 \ntissue injury, which in turn would facilitate lesion implantation. Glandular epithelial cells 354 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n16 \n \nfound in endometrial lesions were shown to produce C3 locally 34. The activity of both 355 \ncomplement cascade members C3 and C4 was higher in serum of women with endometriosis 356 \nthan those without 35. Increased amounts of C1, C3 and C5 were detected in serum 29 and 357 \nperitoneal fluid of women with endometriosis 30,31. Similarly, in lesion-bearing mice, C3 was 358 \nincreased in their peritoneal fluid. Animals with C3 knockdown formed smaller endometrial 359 \ncysts and on average less of them34.  360 \nC3 seems pivotal to endometriosis pathology and given its strong upregulation and presence 361 \nboth in tissue (Fig. 4B) as well as peritoneal fluid of endometriosis-sufferers, it poses an 362 \ninteresting target for early diagnosis and therapy. It has already been proposed as an 363 \nendometriosis serum biomarker. Since in gastric cancer C3 tissue deposition correlated 364 \nnegatively with plasma levels 36, further research is needed to confirm C3 suitability as 365 \nendometriosis biomarker. As far as treatment is concerned, C3 inhibitors have entered clinical 366 \ntrials in anti-ovarian cancer therapy37 and treatment against inflammatory bowel disease. Our 367 \nresults indicate that biomarker and therapeutic potential of C3 should be studied in 368 \nendometriosis in more depth. 369 \n 370 \nOur results revealed strong enrichment in coagulation cascade and showed a dysregulation of 371 \nSERPIN superfamily genes in endometrial lesions (Fig. 3D, Fig. 4D-F, Fig. S4) suggesting an 372 \nimbalance in the coagulation-fibrinolysis processes13. 373 \nSERPINE1 and SERPINE2 were increased in endometrial lesions (Fig. 4D-E). SERPINE1-374 \nencoded PAI-1 was found increased in deep infiltrating lesions 38 and correlated with ovarian 375 \ncancer proliferation and overall poor prognosis 39. PAI-1 inhibition resulted in decreased 376 \nlesion size40. SERPINE2 was implicated in modulating DNA damage response and favoring 377 \ncancer cell invasion 41. Its pro-metastatic activity has been linked to extracellular matrix 378 \nremodeling and increase in matrix metalloproteinase 9 (MMP-9) expression42,43.  379 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n17 \n \nReduction in SERPINA5  expression was linked with an aggressive tumour phenotype and 380 \npoor prognosis in endometrial and ovarian serous carcinomas, in the latter it  was correlated 381 \nwith downstream activation of MMP9 44. Our meta-analysis revealed lower SERPINA5  and 382 \nhigher MMP9 expression in endometrial lesions (Fig. 4F, Fig. S3F). Moreover, ECM 383 \ninteractions were indicated in enrichment analysis (Fig. 3A-B, D). Taken together, our results 384 \nsuggest that the imbalance in coagulation pathway may be affecting extracellular matrix 385 \nremodeling and contributing to metastatic-like potential of endometriotic cells; thereby 386 \npromoting lesion formation. 387 \nJAK/STAT3 pathway inhibition 388 \nOur search for associations between endometriosis gene signature and CMap reference 389 \nperturbagens highlighted the role of inhibitors of JAK, CDK and topoisomerase as possible 390 \ntherapy candidates (Fig. 3E). Our meta-analysis revealed an increased expression of both 391 \nSTAT5A and STAT5B in lesions compared with control tissue (Fig. S3 G-H). 392 \nInterestingly, increased C3 expression was shown to trigger JAK2/STAT3 pathway in gastric 393 \ncancer, which led to subsequent increase of cell proliferation. C3 inhibition with CR1 394 \ndecreased that activation 36. Our results present a similar picture, complement C3 as well as 395 \nJAK/STAT3 pathway seems to play a role in the development of endometriosis. This 396 \nassociation needs further investigation. JAK inhibitors are already used in clinic for other 397 \nautoimmune disease therefore their repurposing should be further tested for endometriosis 398 \ntherapy application.  399 \n 400 \nProposed pathways crosstalk in endometriosis 401 \nIt has been proposed that both complement system and coagulation pathways are tightly 402 \nlinked; coagulation factors have been reported to cleave and activate complement members 403 \nC3 and C545. On the other hand, C3 was shown to protect clots from fibrinolysis 46. Increased 404 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n18 \n \namounts of C3 protein were shown to provoke mast cells activation and various mast cell 405 \nmediators were implicated in the regulation of coagulation and fibrinolysis in anaphylaxis 47. 406 \nOur meta-analysis revealed that endometrial lesions had a higher expression of mast cell 407 \nmarkers including KIT, CP A3 and MS4A6A, FCGR2B  and S100A10  (Fig. S3A-E). An 408 \nincreased mast cells burden was detected previously in animal and human endometrial 409 \ntissue19. Moreover, our results showed that endometrial lesions had a higher level of STAT5A 410 \nand STAT5B (Fig. S5G-H), members of JAK/STAT3 pathway, which regulate mast cells 48. 411 \nTargeting mast cells with JAK inhibitors for alleviation of symptoms of endometriosis has 412 \nbeen proposed almost two decades ago 49 but not much research has been carried out on the 413 \ntopic since. Our current results fill this gap and suggest the use of JAK inhibitors as 414 \nimmunomodulators in endometriosis. Interestingly, a cooperation between mast cells, 415 \ncomplement and coagulation pathways has been reported in an inflammatory disease - 416 \nchronic spontaneous urticaria50. Our analysis indicates that there exists an interplay between 417 \ncomplement and coagulation pathway, mast cells activation, ECM remodeling and 418 \nJAK/STAT3 pathway (summarized in Fig. 5). To the best of authors knowledge, this 419 \nrelationship has not yet been studied in endometriosis and our results warrant a further in-420 \ndepth look into those processes. 421 \n 422 \nStrengths and Limitations 423 \nOur network meta-analysis enabled us to arrive at a consensus endometriosis signature. The 424 \nuse of publicly deposited endometriosis transcriptomic data collected at three different 425 \ncontinents, spanning various ethnicities, age groups as well as various types and stages of 426 \nendometriosis enabled a comprehensive, unbiased and multi-demographic comparison of 427 \nendometriotic and control tissue. 428 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n19 \n \nThe following limitations should be considered when interpreting our results. Our meta-429 \nanalysis included only nine datasets because most of the studies lacked a control group, 430 \nincluded therapeutic intervention or performed RNA isolation on processed tissue. Secondly, 431 \nonly published studies, where the absence of endometriosis was excluded by laparoscopy, 432 \nwere included in this meta-analysis. Therefore, publication bias may have occurred although 433 \nnone was indicated by the funnel plot.  434 \n 435 \nConclusions and Clinical Implications 436 \nWe highlight the role of complement and coagulation cascade in endometriosis and propose 437 \nan interplay between both those processes and mast cells, ECM interaction and JAK/STAT3 438 \npathway that need further investigation. We underscore the significance of C3 and call for 439 \nfurther research into its diagnostic and therapeutic potential. Furthermore, we propose JAK 440 \ninhibitors discovered in drug repurposing analysis and validated in vitro, as potential therapy 441 \ncandidates. 442 \nOur results show differences in expression in eutopic endometrium from patients with and 443 \nwithout endometriosis. Those should be further explored to understand if they contribute to 444 \nendometrial seeding. Detected gene differences may be potential biomarkers that could be 445 \nused in the less invasive endometriosis biopsy and should be further studied. 446 \n 447 \nAcknowledgements 448 \nThis research is part of the project No. 2022/47/P/NZ5/02484 co-funded by the National 449 \nScience Centre and the European Union Framework Programme for Research and Innovation 450 \nHorizon 2020 under the Marie Skłodowska-Curie grant agreement No. 945339. For the 451 \npurpose of Open Access, the author has applied a CC-BY public copyright licence to any 452 \nAuthor Accepted Manuscript (AAM) version arising from this submission;”.  453 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n20 \n \n 454 \nAuthor contributions 455 \nM.A.G, W.M.F and conceived and supervised the study, A.R., M.S. performed GEO database 456 \nsearch, M.A.G., A.R. and M.S. performed study selection, K.S. contributed to database 457 \nsearch, A.R., J. C. performed differential genes expression, A.R., K.S. performed network 458 \nmeta-analysis, M.A.G performed GO and enrichment analysis, M.A.G performed 459 \npharmacogenomic analysis and cell culture in vitro experiments, M.A.G. and AR conducted 460 \nquality control of the data, M.A.G. obtained study funding, M.A.G. and A.R drafted the 461 \nmanuscript, and W.M.F, M.A.G. and A.R revised the manuscript. 462 \n 463 \n 464 \nConflict of Interests 465 \nAuthors declare no conflict of interests. 466 \n 467 \n 468 \nReferences 469 \n1. 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T., Depcrynski, A., Fernando, J. & Ryan, J. J. Mast cell 585 \nhomeostasis and the JAK–STAT pathway. Genes Immun. 11, 599 (2010). 586 \n49. D’cruz, O. J. & Uckun, F. M. Targeting mast cells in endometriosis with janus kinase 587 \n3 inhibitor, JANEX-1. Am. J. Reprod. Immunol. 58, 75–97 (2007). 588 \n50. Yanase, Y., Takahagi, S., Ozawa, K. & Hide, M. The Role of Coagulation and 589 \nComplement Factors for Mast Cell Activation in the Pathogenesis of Chronic 590 \nSpontaneous Urticaria. Cells 10, (2021). 591 \n 592 \n 593 \nFIGURES and LEGENDS 594 \n 595 \nFigure 1. PRISMA flow diagram of Gene Expression Omnibus search for transcriptomic data 596 \ncomparing eutopic and ectopic endometrial tissue. All datasets from ArrayExpress were also 597 \ndeposited in Gene Expression Omnibus thus they were not further considered in the selection 598 \nprocess. 599 \n 600 \nFigure 2. Differentially expressed genes identified by network meta-analysis.  Vo l c a n o  601 \nplots showing differentially expressed genes for the following comparisons (A) endometriotic 602 \nlesions versus endometrium from women with endometriosis, (B) endometriotic lesions 603 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n26 \n \nversus endometrium from women without endometriosis, (C) endometrium from women with 604 \nand without endometriosis. For graphs A to C, red points signify genes with logFC less than -605 \n0.5 or more than 0.5 and p-value less than 0.05, blue points signifiy genes with logFC 606 \nbelonging to -0.5 to 0.5 range and p-value less than 0.05, green points signify genes with 607 \nlogFC less than -0.5 or more than 0.5 and p-value more than 0.05 and grey dots signify genes 608 \nwith with logFC belonging to -0.5 to 0.5 range and p-value more than 0.05. Genes with p-609 \nvalues<1×10−6 and log2FC>|2| (Fig. 2A-B) and p-values<0.05 and log2FC>|0.5|(Fig. 2C) are 610 \nlabelled. Heatmap with top 40 most differentially expressed genes per comparison per dataset 611 \n(D). Expression pattern of differentially expressed genes per comparison type (E). EL – 612 \nendometrial lesion, EEM - eutopic endometrium from women with endometriosis, EH – 613 \neutopic endometrium from women without endometriosis. 614 \nFigure 3. Enriched pathways analysis, functional clustering and computational 615 \npharmacogenomics of DEGs between endometriosis lesions and eutopic endometrium.  616 \nGene ontology analysis using DA VID (A) reveals the importance of inflammation, cell 617 \nadhesion, angiogenesis and ECM remodeling. Metascape enrichment analysis (B) and 618 \nrelationship network of enriched terms visualised in Cytoscape (C) show key events that 619 \ncontribute to endometriosis development. Those include inflammatory and hormonal 620 \nresponse and proliferation and locomotion. Functional annotation clustering reports the 621 \nhighest enrichment score for complement and coagulation cascade, platelet activation, DNA 622 \nremodeling and integrin mediated signaling respectively (D). Top 15 drug candidates 623 \nidentified using a drug repurposing reference database – CMap.  and showing median tau 624 \nvalue above 95. JAK, CDK and topoisomerase inhibitors are identified as potential 625 \npharmacological targets for endometriosis therapy (E). 626 \n 627 \n 628 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\n27 \n \nFigure 4. Differential gene expression across studies for selected genes from the 629 \ncomplement and coagulation pathway for the comparison between EL vs EEM.  Forest 630 \nplot showing the expression of C1QA (complement C1q A chain) - A, C3 (complement C3)  - 631 \nB, C7 (complement C7) - C, SERPINE1 (serpin family E member 1)  - D, SERPINE2 (serpin 632 \nfamily E member 2)  - E, SERPINA5 (serpin family A member 5)  - F. Direct and indirect 633 \ncomparisons from meta-analysis are presented in row number five and six.  The indirect 634 \ncomparisons had a low impact on the combined comparison outcome due to the analyses 635 \nbeing performed on datasets containing comparisons between EL and EEM (Table 2).  636 \n 637 \nFigure 5. A schematic showing key molecular processes contributing to the development 638 \nof lesions.  An interplay between complement and coagulation pathway further influences 639 \nmast cells activation, ECM remodelling and JAK/STAT3 pathway. JAK inhibitors carry 640 \npotential for endometriosis therapy. Genes names in green signify differentially expressed 641 \ngenes for the comparison between EL and EEM. Created in BioRender.com. 642 \n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\nDatabases identified \nthrough GEO searching\n (n = 122)\nDatabases identified for \nscreening\n(n = 104)\nOriginal datasets\n(n = 92)\nDatasets assessed for \neligibility (n = 9) \nDuplicate databases\n (n = 18)\nDatabases excluded due to \nlack of abstracts and/or \narticles (n = 12)\nAnimal datasets (n = 7)\nLack of group with \nendometriosis (n = 18)\nOnly adenomiosis (n = 7)\nWithout control group (n = 6)\nSingle cell (n = 6)\nWithout raw data (n = 5)\nWithout mRNA (n = 4)\nOnly cells/organoids (n = 13)\nSerum (n = 1)\nIdentificationScreeningIncluded\n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\nED\nCBA\n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\nA\nB\nC\nD\nE\n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\nA\n B\nC\n D\nE\n F\n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint \n\nCoagulation cascade\nSerpin \nsuperfamliy\nSERPINE1, SERPINE2, \nSERPINA3, SEPINA5\nECM remodelling\nMMP-9\nComplement cascade\nC3, C1QA, C2, C6, C7\nMast cells\nKIT ,MS4A6A, \nCPA3, FCGR2B,\nS100A10\nJAK/STAT3 pathway\nSTAT5A\nSTAT5B\nP\nP\nJAK inhibitors\nC3\n . CC-BY-NC 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 25, 2025. ; https://doi.org/10.1101/2025.03.25.25324597doi: medRxiv preprint","source_license":"CC0","license_restricted":false}