Flavonoids as Modulators of Lipid Mediator Signaling: A Narrative Review on Mechanisms, Current Evidence, and Gaps in the Literature.

Oxylipins are bioactive lipid mediators derived from polyunsaturated fatty acids that regulate the initiation and resolution of inflammation across the body. Dysregulated oxylipin signaling is implicated in numerous chronic diseases, yet dietary strategies capable of modulating these pathways remain poorly defined. Flavonoids, a diverse class of plant-derived polyphenols, are widely consumed and exhibit anti-inflammatory properties, but their influence on oxylipin metabolism as an integrated network has not been comprehensively evaluated. This narrative review synthesizes current evidence describing how flavonoids and flavonoid-rich foods interact with oxylipin biosynthesis through multiple mechanisms, including modulation of phospholipase activity, remodeling of upstream fatty acid pools, and direct modulation of cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 enzymes. Evidence from in vitro systems, animal models, and emerging human trials suggests that flavonoids can alter oxylipin profiles under conditions of basal, metabolic, inflammatory, and exercise-induced stress, with some studies indicating shifts away from pro-inflammatory species and toward pro-resolving mediator intermediates. However, the literature remains fragmented and heavily weighted toward supraphysiological dosing and limited mediator panels, with minimal assessment of tissue-specific effects or flavonoid metabolites. We highlight critical gaps and propose priorities for future research, emphasizing the need for physiologically relevant flavonoid interventions, comprehensive lipidomics, flavonoid-metabolite profiling, and systems-level integration.