Reprogramming inflammation: Mechanisms and therapeutic targeting of eicosanoids and pro-resolving mediators

Inflammation is a fundamental biological response to infection or tissue injury aimed at restoring homeostasis. While acute inflammation is typically self-limited and resolves through endogenous mechanisms, persistent or dysregulated inflammation underlies many chronic diseases, including atherosclerosis, arthritis, and cancer. Eicosanoids, lipid mediators derived from polyunsaturated fatty acids, orchestrate both the initiation and resolution of inflammation. Their biosynthesis is initiated by phospholipase A₂ (PLA₂) enzymes, which release arachidonic acid from membrane phospholipids, feeding into the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. These pathways generate many bioactive mediators, including pro-inflammatory prostaglandins and leukotrienes, as well as anti-inflammatory and pro-resolving molecules such as lipoxins, resolvins, protectins, and maresins. Notably, the CYP-derived epoxyeicosatrienoic acids (EETs) and their downstream metabolism by soluble epoxide hydrolase (sEH) represent an underappreciated axis in inflammation regulation. Emerging evidence suggests that specialized pro-resolving mediators (SPMs) are not simply anti-inflammatory but act in the low picomolar to nanomolar range to actively promote the resolution phase through immunomodulation, tissue repair, and restoration of barrier function. Aspirin, in addition to its COX-inhibitory effects, can trigger the biosynthesis of epimeric SPMs; however, the concentrations required and their clinical relevance remain under investigation. This review provides a comprehensive analysis of the enzymatic pathways governing eicosanoid biosynthesis, the cellular and molecular events involved in the resolution of inflammation, and current therapeutic strategies aimed at modulating this lipid mediator network. Special attention is given to PLA₂ and sEH as upstream regulatory nodes, as well as to the challenges and prospects of resolution-based pharmacology.