{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:26:12Z","timestamp":1781105172831,"version":"3.54.1"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100016345","name":"Renmin Hospital of Wuhan University","doi-asserted-by":"publisher","award":["WDRM\u201020230410D"],"award-info":[{"award-number":["WDRM\u201020230410D"]}],"id":[{"id":"10.13039\/501100016345","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Endometriosis is a benign yet invasive disease characterized by ectopic endometrial growth and immune remodeling. While emerging evidence implicates cellular senescence in disease progression, the underlying mechanisms remain largely undefined. In this study, we identified marked heterogeneity in senescence across ectopic lesions and observed that P21\u2010activated kinase 4 (PAK4) was consistently upregulated in senescent cells. Mechanistically, senescence induced PAK4 expression, which in turn interacted with AKT and enhanced its phosphorylation, thereby activating the PI3K\/AKT signaling pathway and further amplifying the senescence phenotype. This senescence\u2010PAK4\u2010AKT positive feedback loop ultimately promoted lesion aggressiveness and M2 macrophage polarization. Silencing PAK4 alleviated cellular senescence, attenuated lesion invasiveness, and suppressed immune remodeling. Notably, stigmasterol, a natural phytosterol, effectively downregulated PAK4 expression, disrupted the senescence\u2010AKT feedback loop, and consequently inhibited senescence, invasion, and M2 polarization both in\u00a0vitro and in\u00a0vivo. Together, our findings establish a senescence\u2010driven PAK4\/AKT signaling circuit that fosters an aggressive, immunomodulatory endometriosis subtype and identify stigmasterol as a promising senescence\u2010targeted therapeutic agent.<\/jats:p>","DOI":"10.1111\/acel.70463","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T08:35:30Z","timestamp":1774600530000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Senescence\u2010Driven Remodeling Defines an Aggressive and Immunomodulatory Subtype of Endometriosis"],"prefix":"10.1111","volume":"25","author":[{"given":"Jingchun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuyue","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0718-8726","authenticated-orcid":false,"given":"Jianming","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanzhi","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3841-5557","authenticated-orcid":false,"given":"Li","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106642"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105196"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081011"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2016.01.005"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1549277"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00794"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.09.044"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.21.9532-9542.2005"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2233"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118057"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-024-01972-3"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11510-4"},{"key":"e_1_2_13_14_1","article-title":"HKDC1, a Target of TFEB, Is Essential to Maintain Both Mitochondrial and Lysosomal Homeostasis, Preventing Cellular Senescence","volume":"121","author":"Cui M.","year":"2024","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1FO02493K"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13574"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmz047"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153415"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113317"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2969"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa045"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dey332"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-01890-1"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm13091284"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-07045-2"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24020914"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052476"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052476"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154728"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202415285"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102926"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04843-4"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-022-02500-3"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179274"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmz018"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.28681"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.05.020"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2023.108913"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02085-3"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.72952"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-16629-x"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04209-0"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-024-03768-5"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-022-00901-w"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06467-2"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.629008"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-023-01886-3"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1810764"}],"updated-by":[{"DOI":"10.1111\/acel.70584","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000}}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70463","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70463","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70463","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T16:48:12Z","timestamp":1781023692000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":47,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1111\/acel.70463"],"URL":"https:\/\/doi.org\/10.1111\/acel.70463","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"2025-07-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70463"}}