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Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen\u2010induced sterile inflammation regulates EH remains unclear. Here, a single\u2010cell RNA\u2010Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1\u03b2 and TNF\u03b1 from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell\u2013macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA\u2010Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1\n                    <jats:sup>Tyr380<\/jats:sup>\n                    . This event activates downstream activator protein 1 (AP\u20101) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial\u2010specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol\u2010driven acute inflammation to macrophage\u2010amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202403038","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T06:50:15Z","timestamp":1725519015000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["SHP2\u2010Triggered Endothelial Cell Activation Fuels Estradiol\u2010Independent Endometrial Sterile Inflammation"],"prefix":"10.1002","volume":"11","author":[{"given":"Jie","family":"Pan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Qu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"},{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University  209 Tongshan Road Xuzhou Jiangsu 221004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhui","family":"Zhai","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjia","family":"Tan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School School of Life Sciences Nanjing University  163 Xianlin Avenue Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianming","family":"Du","sequence":"additional","affiliation":[{"name":"General Clinical Research Center Nanjing First Hospital Nanjing Medical University  Nanjing 210006 China"},{"name":"School of Basic Medicine &amp; 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