Eicosanoid and specialized pro-resolving mediator pathways (SPM pathways)

The eicosanoid and specialized pro-resolving mediator (SPM) pathways are complex metabolic networks that convert polyunsaturated fatty acids (PUFAs), such as arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), into bioactive lipid signaling molecules [1]. Eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are primarily synthesized via cyclooxygenase (COX) and lipoxygenase (LOX) enzymes and serve as critical initiators of the acute inflammatory response, mediating pain, fever, and vascular permeability [2]. Conversely, SPMs—comprising lipoxins, resolvins, protectins, and maresins—are produced during the resolution phase of inflammation to actively terminate leukocyte infiltration, promote the clearance of apoptotic cells by macrophages, and facilitate tissue repair [3]. Chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and atherosclerosis, are often characterized by an imbalance in these pathways, where pro-inflammatory eicosanoids predominate over pro-resolving mediators [4]. Therapeutic interventions targeting these pathways include widely used non-steroidal anti-inflammatory drugs (NSAIDs) and leukotriene receptor antagonists, as well as emerging resolution-based therapies that utilize synthetic SPM analogs to restore physiological homeostasis [5].

Other names

Arachidonic acid cascadeOxylipin signalingLipid mediator pathwaysPro-inflammatory and pro-resolving lipid signalingPUFA-derived mediator pathways

Drugs targeting these pathways act by inhibiting key biosynthetic enzymes such as cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX), or by antagonizing receptors like the cysteinyl leukotriene receptor 1 (CysLT1). Emerging therapies aim to activate pro-resolving G protein-coupled receptors (GPCRs) such as ALX/FPR2 and ChemR23 to promote the resolution of inflammation [1, 5].