The dual pathological roles and targeted therapy of PGE₂: from receptor signaling networks to disease...

Prostaglandin E₂ (PGE₂) is a pleiotropic lipid mediator that exerts context-dependent effects via four G protein-coupled receptors (EP1-EP4), 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 PGE₂ across these diseases. In neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, PGE₂ 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, PGE₂ 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, PGE₂ 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 PGE₂ 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 PGE₂ signaling network.