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We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects \u03b2-cells from cytokine-mediated death ex vivo and relieves oxidative stress and maintains \u03b2-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated \u03b2-cell death in islets from nonobese diabetic (NOD) mice. Because PGE2 can also alter immune cell phenotypes, we tested whether EP modulation prevents \u03b2-cell destruction in a setting of aggressive autoimmunity in\u00a0vivo. Simultaneous blockade of the inhibitory EP3 receptor and activation of the stimulatory EP4 receptor delayed onset of hyperglycemia, prevented loss of \u03b2-cell mass, and reduced insulitis in cyclophosphamide-treated female NOD mice. Despite reduced insulitis, there were no changes in several systemic T-cell populations, including regulatory T cells. However, EP modulation altered islet cytokine expression and, within \u03b2-cells, preserved identity, sustained activation of the antioxidant factor NRF2, and reduced evidence of senescence. Thus, the PGE2 signaling pathway is a potential target for protecting \u03b2-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Modulation of prostaglandin E2 (PGE2) signaling improves \u03b2-cell health and survival. In this study, we examined whether these \u03b2-cell effects could be harnessed alongside known PGE2-mediated immunomodulation to ameliorate \u03b2-cell loss in a model of severe islet autoimmunity. Simultaneous pharmacological blockade of the EP3 receptor and activation of the EP4 receptor maintain mature \u03b2-cell mass, ameliorate the proinflammatory insulitic microenvironment, and alter \u03b2-cell stress responses in female nonobese diabetic mice undergoing aggressive inflammatory assault. EP modulation shows promise to support \u03b2-cell resiliency and reduce inflammation in a setting of autoimmune attack, such as type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1007","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:10:23Z","timestamp":1785514223000},"page":"1823-1836","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Dual Modulation of Prostaglandin E2 Receptors EP3 and EP4 Protects \u03b2-Cell Mass in a Model of Aggressive Autoimmune Inflammation"],"prefix":"10.2337","volume":"75","author":[{"given":"Juliann B.","family":"Burkett","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University 1 , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Fuhr","sequence":"additional","affiliation":[{"name":"Department of Medicine, 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