{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:06:50Z","timestamp":1792793210727,"version":"4.5.0"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Prostaglandin E\n                    <jats:sub>2<\/jats:sub>\n                    (PGE\n                    <jats:sub>2<\/jats:sub>\n                    ) is a pleiotropic lipid mediator that exerts context-dependent effects via four\u00a0G protein-coupled receptors (EP1\u2013EP4), playing a pivotal role in the pathogenesis of diverse disorders, including neurodegenerative, cardiovascular, neoplastic, and chronic inflammatory diseases. In this review, we systematically delineate the dualistic functions and mechanisms of PGE\n                    <jats:sub>2<\/jats:sub>\n                    across these diseases. In neurodegenerative conditions such as Alzheimer\u2019s and Parkinson\u2019s diseases, PGE\n                    <jats:sub>2<\/jats:sub>\n                    exacerbates neuroinflammation and neuronal injury in part through EP1 and EP2 in specific cell types, whereas EP4 signaling can confer neuroprotection in certain disease-stage and cellular contexts. Within the tumor microenvironment, PGE\n                    <jats:sub>2<\/jats:sub>\n                    can drive immunosuppression, angiogenesis, and tumor progression via the EP2\/EP4 axis, particularly in colorectal carcinoma, lung adenocarcinoma, and melanoma where this axis is best characterized. In cardiovascular and metabolic diseases, PGE\n                    <jats:sub>2<\/jats:sub>\n                    exhibits both protective (EP4-mediated) and detrimental (EP3-mediated) effects. Building on this mechanistic framework, we highlight emerging therapeutic strategies designed to overcome the limitations of conventional non-steroidal anti-inflammatory drugs (NSAIDs). These include modulating key enzymes involved in PGE\n                    <jats:sub>2<\/jats:sub>\n                    synthesis and degradation, developing subtype-selective EP receptor modulators for context-specific intervention, and synergistically targeting downstream pathogenic signaling pathways (e.g., PI3K\/Akt\/mTOR). By integrating mechanistic and translational perspectives, this review aims to advance next-generation therapies targeting the PGE\n                    <jats:sub>2<\/jats:sub>\n                    signaling network.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1810417","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:47:04Z","timestamp":1784090824000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The dual pathological roles and targeted therapy of PGE2: from receptor signaling networks to disease microenvironment modulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Mingming","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Binhai County People\u2019s Hospital","place":["Yancheng, Jiangsu, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Niu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xue","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University","place":["Nantong, Jiangsu, 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