{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:14:59Z","timestamp":1789647299123,"version":"4.0.0"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Endometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by\u00a0systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called \u2018\n                      <jats:italic>END\u2019<\/jats:italic>\n                      , that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Na\u00efve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene\n                      <jats:italic>AKT1<\/jats:italic>\n                      . In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as\n                      <jats:italic>ESR1<\/jats:italic>\n                      . Such analysis was supported by current interests targeting the PI3K\/AKT\/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting\n                      <jats:italic>ESR1<\/jats:italic>\n                      are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly \ufeffdisease-modifying anti-rheumatic drugs (such as\n                      <jats:italic>TNF<\/jats:italic>\n                      ,\n                      <jats:italic>IL6<\/jats:italic>\n                      and\n                      <jats:italic>IL6R<\/jats:italic>\n                      blockades, and\n                      <jats:italic>JAK<\/jats:italic>\n                      inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation \u2013 the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Improved target prioritization, along with an atlas of\n                      <jats:italic>in silico<\/jats:italic>\n                      predicted targets and repurposed drugs (available at\n                      <jats:uri>https:\/\/23verse.github.io\/end<\/jats:uri>\n                      ), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2022.758440","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T15:02:27Z","timestamp":1648479747000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation"],"prefix":"10.3389","volume":"13","author":[{"given":"Chaohui","family":"Bao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengru","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/PAP.0b013e3180ca7d7b","article-title":"The Pathology of Endometriosis: A Survey of the Many Faces of a Common Disease Emphasizing Diagnostic Pitfalls and Unusual and Newly Appreciated Aspects","volume":"14","author":"Clement","year":"2007","journal-title":"Adv Anat Pathol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.041","article-title":"Endometriosis: Etiology, Pathobiology, and Therapeutic Prospects","volume":"184","author":"Saunders","year":"2021","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41572-018-0008-5","article-title":"Endometriosis","volume":"4","author":"Zondervan","year":"2018","journal-title":"Nat Rev Dis Prim"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00389-5","article-title":"Endometriosis Is a Chronic Systemic Disease: Clinical Challenges and Novel Innovations","volume":"397","author":"Taylor","year":"2021","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1095\/biolreprod.116.142877","article-title":"Low Body Mass Index in Endometriosis is Promoted by Hepatic Metabolic Gene Dysregulation in Mice","volume":"95","author":"Goetz","year":"2016","journal-title":"Biol Reprod"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2015.10.030","article-title":"Risk of Developing Major Depression and Anxiety Disorders Among Women With Endometriosis: A Longitudinal Follow-Up Study","volume":"190","author":"Chen","year":"2016","journal-title":"J Affect Disord"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1603582","article-title":"The Systemic Effects of Endometriosis","volume":"35","author":"Alderman","year":"2017","journal-title":"Semin Reprod Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1093\/humupd\/dmz012","article-title":"The Association Between Endometriosis and Autoimmune Diseases: A Systematic Review and Meta-Analysis","volume":"25","author":"Shigesi","year":"2019","journal-title":"Hum Reprod Update"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms15539","article-title":"Meta-Analysis Identifies Five Novel Loci Associated With Endometriosis Highlighting Key Genes Involved in Hormone Metabolism","volume":"8","author":"Sapkota","year":"2017","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3314","article-title":"The Support of Human Genetic Evidence for Approved Drug Indications","volume":"47","author":"Nelson","year":"2015","journal-title":"Nat Genet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pgen.1008489","article-title":"Are Drug Targets With Genetic Support Twice as Likely to be Approved? 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