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This review highlights how the highly immunosuppressive tumor microenvironment limits success. It focuses on metformin, an antidiabetic drug investigated preclinically and clinically, describing how AMPK pathway activation can modulate ovarian cancer cell growth, survival, and tumor microenvironment phenotypes, including macrophages and T cells.",{"@graph":14,"@context":71},[15,34,54],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/metformin-a-type-2-diabetes-mellitus-drug-and-ovarian-cancer-anticancer-mechanisms-and-therapeutic-implications/350028/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":48,"encodingFormat":47,"isAccessibleForFree":49,"interactionStatistic":50},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/metformin-a-type-2-diabetes-mellitus-drug-and-ovarian-cancer-anticancer-mechanisms-and-therapeutic-implications/350028.png","ImageObject",300,407,{"name":42,"@type":43},"Jake","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-09-22",true,{"@type":51,"interactionType":52,"userInteractionCount":22},"InteractionCounter",{"@type":53},"ViewAction",{"@type":55,"mainEntity":56},"FAQPage",[57,63,67],{"name":58,"@type":59,"acceptedAnswer":60},"Why are new ovarian cancer therapies needed despite existing treatments?","Question",{"text":61,"@type":62},"Ovarian cancer is often diagnosed late, and even with surgery and chemotherapy (and newer options such as PARP inhibitors), resistance commonly develops, leading to poor overall survival. The immunosuppressive tumor microenvironment also hampers successful treatment.","Answer",{"name":64,"@type":59,"acceptedAnswer":65},"What role does metformin play in ovarian cancer therapy?",{"text":66,"@type":62},"Metformin has been studied as an antitumor agent in preclinical studies and clinical trials. It can affect cancer cell growth and survival by activating the AMPK pathway and can also influence other tumor microenvironment cells such as macrophages and T cells.",{"name":68,"@type":59,"acceptedAnswer":69},"What characterizes epithelial ovarian cancer and high-grade serous ovarian cancer (HGSOC)?",{"text":70,"@type":62},"Epithelial ovarian cancer makes up about 90% of cases. HGSOC is the most common epithelial subtype, often diagnosed at later stages due to asymptomatic progression and marked by frequent recurrence, poor differentiation, limited estrogen receptor expression, and typical detection at stage III–IV.","https://schema.org",{"og:url":32,"og:type":73,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":75,"canonical":32},"index,follow",{"doc_id":77,"site_id":7},350028,1790114458,{"code":4,"msg":80,"data":81},"success",[82,86,90,94,99,104,108,113,118,121,125],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":83,"show_sort_weight":84,"slug":85},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":87,"show_sort_weight":88,"slug":89},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":91,"show_sort_weight":92,"slug":93},"Exam",70,"exam",{"id":95,"doc_module":4,"doc_module_name":25,"category_name":96,"show_sort_weight":97,"slug":98},5,"Comic",60,"comic",{"id":100,"doc_module":4,"doc_module_name":25,"category_name":101,"show_sort_weight":102,"slug":103},6,"Technology",50,"technology",{"id":105,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":106,"slug":107},7,40,"healthcare",{"id":109,"doc_module":4,"doc_module_name":25,"category_name":110,"show_sort_weight":111,"slug":112},8,"Research & Report",30,"research-report",{"id":114,"doc_module":4,"doc_module_name":25,"category_name":115,"show_sort_weight":116,"slug":117},9,"Religion & Spirituality",20,"religion-spirituality",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":119,"show_sort_weight":116,"slug":120},"World Cup","world-cup",{"id":122,"doc_module":4,"doc_module_name":25,"category_name":123,"show_sort_weight":122,"slug":124},10,"Lifestyle","lifestyle",{"id":126,"doc_module":4,"doc_module_name":25,"category_name":127,"show_sort_weight":95,"slug":128},19,"General","general",{"code":4,"msg":80,"data":130},{"doc_id":77,"user_id":131,"nickname":42,"user_avatar":132,"doc_module":4,"category_id":105,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":22,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":138,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144},962084928904,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Review  \nMetformin—A Type 2 Diabetes Mellitus Drug—And Ovarian Cancer: Anticancer Mechanisms and Therapeutic Implications  \nEmma Sielski 1,†, Al-Noumani Shuhd 2,†, Ella Bower 1, Kate Cunningham 1, Grace Beidel 1, Alissa Luchianova 1, Maria Cecilia Courreges 3 and Fabian Benencia 1,2,4,5,6, *  \nAcademic Editor: Raquel Soares  \nReceived: 23 December 2025  \nRevised: 28 February 2026  \nAccepted: 7 March 2026  \nPublished: 11 March 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Department of Biomedical Sciences, College of Osteopathic Medicine, Academic Research Center, Ohio University, Athens, OH 45701, USA; [es099121@ohio.edu](es099121@ohio.edu) (E.S.); [gb311522@ohio.edu](gb311522@ohio.edu) (G.B.); [al604022@ohio.edu](al604022@ohio.edu) (A.L.)  \n2 Biomedical Engineering Program, Department of Chemical and Biomolecular Engineering, Russ College of Engineering and Technology, Ohio University, Athens, OH 45701, USA; [sa489020@ohio.edu](sa489020@ohio.edu)  \n3 Clinical and Translational Research Unit, Research and Grants, HCOM, Ohio University, Athens, OH 45701, USA  \n4 Molecular and Cell Biology Program, Ohio University, Athens, OH 45701, USA  \n5 Diabetes Institute, Ohio University, Athens, OH 45701, USA  \n6 Institute for Molecular Medicine and Aging, Ohio University, Athens, OH 45701, USA  \n* [Correspondence: benencia@ohio.edu](Correspondence: benencia@ohio.edu); Tel.: +1-740-597-2133 † These authors contributed equally to this work.  \nAbstract  \nOvarian cancer is a devastating disease that is often diagnosed in the late stages. The typical therapeutic approach includes surgery plus cytotoxic drugs such as carboplatin and paclitaxel. In recent years, the advent of poly ADP-ribose polymerase (PARP) inhibitors such as olaparib has offered additional treatment opportunities for patients with BRCA mutations or homologous recombination deficiencies. Nevertheless, resistance to therapy usually occurs, leading to poor overall survival. Therefore, novel treatments are needed for this disease. One of the obstacles to successful treatment is the highly immunosuppressive nature of the ovarian cancer microenvironment. Recent strategies for the treatment of ovarian cancer and other types of cancer involve targeting the metabolism of cancer cells and other cells of the tumor microenvironment. One drug that has been investigated both in preclinical studies and clinical trials as an antitumor agent is metformin. This drug, typically used for the treatment of type-2 diabetes for its capability to lower blood glucose, can directly affect cancer cell growth and survival by activating the AMPK (adenosine monophosphate-activated protein kinase) pathway. Furthermore, it can affect the phenotype of other cells of the tumor microenvironment such as macrophages and T cells. In this review, we summarize the main characteristics of ovarian cancer and describe preclinical studies and clinical trials involving metformin as a therapeutic agent for this disease.  \nKeywords: metformin; type-2 diabetes mellitus; high-grade ovarian cancer; tumor microenvironment; chemotherapy  \n1. Introduction  \nAccording to the World Cancer Research Fund, in 2022 there were about 320,000 new cases of ovarian cancer, with the USA, India and China harboring the highest number of them. The American Cancer Society estimates that in 2025 about 20,000 women received a diagnosis of ovarian cancer in the USA, and that around 13,000 will die from this disease. Epithelial ovarian cancer (EOC) accounts for approximately 90% of ovarian cancer cases  \nand is characterized by presentation at late stages, resulting in poor survival outcomes, with about 40% and 20% of women on average surviving less than 5 years after diagnosis (stage III and IV, respectively) [1] . Therefore, there is a need for novel therapeutic approaches for thi","cbCaihoFkohcVj7D","https://ap.wps.com/l/cbCaihoFkohcVj7D","pdf",2594805,33,"English","# Abstract\n# 1. Introduction\n# 2. Epithelial Ovarian Cancer Generalities and Treatment","[{\"question\":\"Why are new ovarian cancer therapies needed despite existing treatments?\",\"answer\":\"Ovarian cancer is often diagnosed late, and even with surgery and chemotherapy (and newer options such as PARP inhibitors), resistance commonly develops, leading to poor overall survival. The immunosuppressive tumor microenvironment also hampers successful treatment.\"},{\"question\":\"What role does metformin play in ovarian cancer therapy?\",\"answer\":\"Metformin has been studied as an antitumor agent in preclinical studies and clinical trials. It can affect cancer cell growth and survival by activating the AMPK pathway and can also influence other tumor microenvironment cells such as macrophages and T cells.\"},{\"question\":\"What characterizes epithelial ovarian cancer and high-grade serous ovarian cancer (HGSOC)?\",\"answer\":\"Epithelial ovarian cancer makes up about 90% of cases. HGSOC is the most common epithelial subtype, often diagnosed at later stages due to asymptomatic progression and marked by frequent recurrence, poor differentiation, limited estrogen receptor expression, and typical detection at stage III–IV.\"}]","Metformin—A Type 2 Diabetes Mellitus Drug - And Ovarian Cancer: Anticancer Mechanisms and Therapeutic Implications | PDF",1790086823,83]