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While kisspeptin shows anti-invasive and anti-angiogenic effects in multiple cancers, its EMs-specific inhibitory mechanism through the KISS1 receptor remains unclear. This study used RNA sequencing to compare ectopic and eutopic endometrium across patients and identified progressively altered genes, highlighting KISS1R and enrichment in the PI3K/AKT pathway. Functional validation via animal and cell experiments indicated CREB5-dependent suppression of PI3K/AKT phosphorylation, reducing endometrial cell invasion and angiogenesis.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/kisspeptins-inhibit-ectopic-endometrial-cell-invasion-and-angiogenesis-by-suppressing-pi3kakt-signaling-pathway-via-creb5-in-endometriosis/407244/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/kisspeptins-inhibit-ectopic-endometrial-cell-invasion-and-angiogenesis-by-suppressing-pi3kakt-signaling-pathway-via-creb5-in-endometriosis/407244.png","ImageObject",300,407,{"name":92,"@type":93},"Eliana","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address in endometriosis?","Question",{"text":112,"@type":113},"The study addresses how endometriosis progresses from ectopic implantation and requires invasion and angiogenesis, and specifically seeks the regulatory mechanism involving kisspeptin signaling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers identify candidate genes and pathways?",{"text":117,"@type":113},"They performed comparative transcriptomic analysis of ectopic versus eutopic endometrium and screened for genes with progressively altered expression patterns, followed by KEGG pathway enrichment focusing on PI3K/AKT.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism do the results support for CREB5, PI3K/AKT, and cell behaviors?",{"text":121,"@type":113},"The findings support that kisspeptin/KISS1R suppresses endometrial cell invasion and angiogenesis by increasing CREB5 and reducing phosphorylation of PI3K and AKT, consistent with effects on the PI3K/AKT pathway.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},407244,1791013353,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36,"preview_page_count":4},4398048949847,"https://ap-avatar.wpscdn.com/avatar/400002536579ef2da7f?_k=1778318612642679267","Ivyspring  \nInternational Publisher  \nInternationalJournal of Medical Sciences  \n2026; 23(1): 334-349. doi: 10.7150/ijms.112890  \nResearch Paper  \nKisspeptins inhibit ectopic endometrial cell invasion and angiogenesis by suppressing PI3K/AKT signaling pathway via CREB5 in endometriosis  \nLingnan Kong, MS1\\#; Suliya Yushanjiang, BS2\\#; Li Nie, PhD1; Yiran Pan1; Lei Jin 1; Zun Wang1; Man He1; Gao Zhang1; Ziyang Ma, MS1; Rongqian Zhao1; Dongzhi Yuan, PhD1􀀍; Changlong Li, PhD1􀀍  \n1. West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.  \n2. Department of Public Health Laboratory Sciences, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.  \n\\# These authors contributed equally to this work.  \n􀀍 Corresponding authors: Dongzhi Yuan, Changlong Li, Institution: West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University. Address: 17 Section 3, South Renmin Road, Chengdu 610041 P. R. China. Tel: +86-28 8550 3410; Fax: +86-28 8550 3204; E-mail: [yuandongzhi@scu.edu.cn](yuandongzhi@scu.edu.cn); [changlongli@scu.edu.cn. ORCID:](changlongli@scu.edu.cn. ORCID:) 0000-0002-6653-4529; 0009-0009-0699-0731.  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2025.02.26; Accepted: 2025.11.14; Published: 2026.01.01  \nAbstract  \nEndometriosis (EMs) is a common gynecological disorder. According to the most widely recognized theory of retrograde menstruation, endometrial cells require completion of three key steps during ectopic implantation: adhesion, invasion, and angiogenesis. Although kisspeptin exerts anti-invasive and anti-angiogenic effects in multiple tumors, its potential inhibitory effects mediated through the KISS1 receptor (KISS1R) on EMs-related invasion and angiogenesis remain uncharacterized. This study aimed to identify regulatory genes in EMs pathogenesis via RNA sequencing and elucidate underlying molecular mechanisms. We performed a comparative transcriptomic analysis of ectopic endometrium (EC) and eutopic endometrium (EU) in 5 patients with EMs and control endometrium in 3 women without EMs. Then, we screened for genes that showed significant differences between EU and group, and even more pronounced differences between EC and EU, indicating a progressive change. Moreover, we identified the top 20 progressively altered genes during EMs development, including KISS1R. Furthermore, KEGG pathway analysis revealed that these progressively altered DEGs were mainly enriched in thephosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. Previous studies suggest that the PI3K/AKT signaling pathway may mediate cell invasion and angiogenesis in EMs. Additionally, substantial evidence indicates that cAMP-response element binding protein (CREB5), a transcriptional regulator, can regulate the PI3K/AKT pathway. However, the mechanism of functional changes of CREB5 and PI3K/AKT in EMs is unclear. Our study validated the functional role of KISS1/KISS1R in EMs through animal experiments and cell experiments. It may suppress the cell invasion and angiogenesis of endometrial cells by reducing the phosphorylation levels of PI3K and AKT mediated by increasing CREB5 . This mechanistic insight provides novel pathogenic explanations for EMs.  \nKeywords: endometriosis; KISS1; PI3K/AKT signaling pathway; cell invasion; angiogenesis  \n1. Introduction  \nEndometriosis (EMs) is a common gynecological disorder characterized by ectopic implantation of active endometrial cells [1] . It affects approximately 10% of women of childbearing age, causing dysmenorrhea, chronic pelvic pain and infertility [2] . Epidemiological data reveal that the incidence of ","cbCaibB4u7ptoGKq","https://ap.wps.com/l/cbCaibB4u7ptoGKq","pdf",13138784,16,"English","# Introduction\n## Endometriosis background and implantation steps\n## Kisspeptins and KISS1/KISS1R in disease context\n# Abstract Overview\n## Study design and comparative transcriptomics\n## Identification of progressively altered genes and pathway enrichment\n## Functional validation and proposed mechanism","[{\"question\":\"What problem does the study address in endometriosis?\",\"answer\":\"The study addresses how endometriosis progresses from ectopic implantation and requires invasion and angiogenesis, and specifically seeks the regulatory mechanism involving kisspeptin signaling.\"},{\"question\":\"How did the researchers identify candidate genes and pathways?\",\"answer\":\"They performed comparative transcriptomic analysis of ectopic versus eutopic endometrium and screened for genes with progressively altered expression patterns, followed by KEGG pathway enrichment focusing on PI3K/AKT.\"},{\"question\":\"What mechanism do the results support for CREB5, PI3K/AKT, and cell behaviors?\",\"answer\":\"The findings support that kisspeptin/KISS1R suppresses endometrial cell invasion and angiogenesis by increasing CREB5 and reducing phosphorylation of PI3K and AKT, consistent with effects on the PI3K/AKT pathway.\"}]","Kisspeptins inhibit ectopic endometrial cell invasion and angiogenesis by suppressing PI3K/AKT signaling pathway via CREB5 in endometriosis | PDF",1790572211]